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WO2009112445A1 - Procédé d’accroissement de phosphatidyl-choline des cellules par l’inhibition de la dgat1 - Google Patents

Procédé d’accroissement de phosphatidyl-choline des cellules par l’inhibition de la dgat1 Download PDF

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Publication number
WO2009112445A1
WO2009112445A1 PCT/EP2009/052701 EP2009052701W WO2009112445A1 WO 2009112445 A1 WO2009112445 A1 WO 2009112445A1 EP 2009052701 W EP2009052701 W EP 2009052701W WO 2009112445 A1 WO2009112445 A1 WO 2009112445A1
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phenyl
pyridin
cyclohexyl
acetic acid
oxadiazol
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PCT/EP2009/052701
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Avirup Bose
James Thompson
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • DGAT1 Diacylglycerol acyl transferase 1
  • Phosphatidylcholine is a phospholipid class that forms a large fraction of cellular membranes and secreted lipoproteins in humans.
  • Phosphatidylcholine is synthesized in vivo by the reaction of cytidine-diphosphocholine (CDP-choline) with diacylglycerol (DAG); this reaction is enzymatically catalyzed by CDP-choline: 1 ,2-diacylglycerol phosphocholine transferase (Kent C, Biochim. Biophys. Acta, 1733: 53-66, 2005).
  • DAG is a metabolic intermediate that can be converted to either phospholipids or triglycerides ( Figurei ) by different enzymatically catalyzed reactions (Coleman RA, Prog. Lipid Res., 34: 134-176, 2004).
  • Figurei The structural properties of phosphatidylcholine in lipid bilayers have been studied by calorimetric and X-ray crystallographic methods (Goni FM, et al. Prog. Lipid Res. 38: 1-48, 1999).
  • the choline moeity of phosphatidylcholine can be removed by phospholipase D to produce phosphatidic acid, a lipid that can act as a second messenger during cellular signal tranduction (Jenkins GM, et al., Cell. MoI. Life Sci. 62: 2305-2316, 2005); action of phospholipase C on phosphatidylcholine produces DAG in intracellular locations that activate protein kinase C (among other events) and leads to a host of different effects (Becker KP, et al. Cell MoI. Life Sci. 62: 1448-1461 , 2005).
  • HDL high density lipoprotein
  • phosphatidylcholine is a component of high density lipoprotein (HDL), which is a key component of the mammalian reverse cholesterol transport system.
  • HDL high density lipoprotein
  • Current understanding of reverse cholesterol transport indicates that HDL is first secreted as a cholesterol deficient discoid particle, comprised principally of phospholipids and apolipoprotein A1 , which can remove cholesterol effluxed from tissues and transport it to the liver for excretion.
  • the liver is also the primary site of HDL biosynthesis and secretion, but the intestine is also capable of producing HDL and may play a role in the cardiovascular protection afforded by reverse cholesterol transport (Kruit JK, et al., World J.
  • Phosphatidylcholine has also been shown to be deficient in the intestinal mucosa of patients with ulcerative colitis compared to healthy volunteers (Ehehalt R, Scand. J. of Gastroenterology, 39: 737-742). Orally dosed preparations of phosphatidylcholine have been shown to be efficacious in treating symptoms of ulcerative colitis in humans (Stremmel W, Gut, 54: 966-971 , 2005). Some insight into the mechanism by which exogenous phosphatidylcholine might ameliorate colitis symptoms was obtained by exposing the Caco-2 colon carcinoma cell line to the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the presence and absence of phosphatidylcholine.
  • TNF-alpha tumor necrosis factor-alpha
  • TNF-alpha activation of the proinflammatory protein kinase signal transduction cascades and the resulting increases in gene expression were all reduced relative to controls by phosphatidylcholine treatment of Caco-2 cells (Treede I, J. Biol. Chem., 282: 27155- 27164, 2007).
  • DGAT is an enzyme that catalyzes the last step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of a 1 ,2-diacylglycerol with a fatty acyl-CoA resulting in Coenzyme A and triacylglycerol.
  • DGAT1 acyl coA-diacylglycerol acyl transferase 1 , see Cases et al, Proc. Natl. Acad. Sci. 95:13018-13023, 1998)
  • DGAT2 acyl coA-diacylglycerol acyl transferase 2, see Cases et al, J. Biol.
  • DGAT1 and DGAT2 do not share significant protein sequence homology. Importantly, DGAT1 knockout mice are protected from high fat diet-induced weight gain and insulin resistance (Smith et al, Nature Genetics 25:87-90, 2000). The phenotype of the DGAT1 knockout mice suggests that a DGAT1 inhibitor has utility for the treatment of obesity and obesity-associated complications.
  • FIG. 1 Biosynthetic pathway for phosphatidylcholine and triacylglycerol; MGAT, monoacylglycerol acyltransferase; CTP, CDP-choline: diacylglycerol phosphocholine transferase; DGAT, diacylglycerol acyltransferase; LPAAT, lysophosphatidic acid acyltransferase; GPAT, glycerol-3-phosphate acyltransferase.
  • Figure 2 Effect of DGAT1 inhibition by ⁇ 5-[2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5- yl]-[1 ,3,4]oxadiazol-2-yl]-(6-methoxy-pyridin-3-yl)-amine on triglyceride and phosphatidylcholine biosynthesis in C2C12 cells.
  • Ulcerative colitis patients have been found to have lower levels of phosphatidylcholine in the intestinal mucosa relative to healthy control subjects. Orally dosed preparations of phosphatidylcholine have been found to relieve some ulcerative colitis symptoms and in vitro these preparations inhibit the proinflammatory effects of tumor necrosis factor alpha.
  • the present invention discloses that inhibition of DGAT1 in a tissue culture line in the presence of exogenous fatty acid leads to incorporation of the exogenous fatty acid into phosphatidylcholine.
  • orally active or parenterally administered DGAT1 inhibitors provide a novel approach to treatment of ulcerative colitis.
  • HDL high density lipoprotein
  • C2C12 cells were from ATCC and cultured in 24 mM glucose DMEM (Dulbecco's Minimal Essential Medium) supplemented with 10% FBS and 1 % penicillin and streptomycin. C2C12 cells were plated in 96 well plates at density of eighteen thousand cells/well in DMEM 0.5 mM glucose supplemented with 10% FBS and 1% penicillin and streptomycin (seeding medium) 24 hours before the assay. BSA conjugated 13 Ci 8 oleate was diluted to 250 ⁇ M in DMEM at 5 mM glucose supplemented with 10% FBS and 1 % penicillin and streptomycin (assay medium) and 500 ⁇ l was transferred to each well of a 96 well plate.
  • glucose DMEM Dulbecco's Minimal Essential Medium
  • FBS penicillin and streptomycin
  • ⁇ 5-[2-(2,6-dichloro-phenyl)-3H-benzoimidazol- 5-yl]-[1 ,3,4]oxadiazol-2-yl]-(6-methoxy-pyridin-3-yl)-amine was added to assay medium in a 96 well plate. The plate was covered and shaken to mix compound with assay media. Seeding media was removed from the cells and replaced with 100 ⁇ l assay media containing the ⁇ 5-[2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1 ,3,4]oxadiazol- 2-yl]-(6-methoxy-pyridin-3-yl)-amine.
  • Mass Spectrometric Analysis A 5- ⁇ L aliquot of extract was injected into a 100- ⁇ L / min stream of a solvent, comprised of 95% methanol, 5% water v/v, containing 25 mM ammonium acetate, which flowed into the ionization source of an electrospray ionization mass spectrometer.
  • a constant neutral mass loss scan measured the losses of neutral fatty acids from the [M+NH 4 ] + cations of the cellular triglycerides. Consecutive scans at differing mass loss settings recorded each expected fatty acid expected to occur in the triglyceride pool, as follows. Quantitation was effected by measuring the ion count attributable fatty acid loss peaks.
  • a scan measuring the parent masses of m/z 184 specifically identifies the Phosphatidyl Choline [M+H] + protonated molecules.
  • the inhibitor concentration response of triglyceride synthesis was fit to equation 2 to determine the IC 50 of the inhibitor.
  • Phosphatidylcholine was measured by normalizing the ion count for phosphatidylcholine containing two 13 C 18 oleate chains to that of phosphatidylcholine containing an oleate chain and a palmitate chain.
  • the inhibitor concentration dependence of the phosphatidylcholine ratio was fitted to equation 3 to determine the EC 5 O of the inhibitor.
  • I E-quation 3 n %/act ⁇ •v ⁇ •ty M ⁇ . r ax - Max - Min
  • Tumor necrosis factor alpha is a proinflammatory cytokine which has been neutralized in vivo with soluble receptors and antibodies in the context of inflammatory bowel diseases (TiIg H, et al. Expert Opin. Biol. Ther. 7: 1051-1059 (2007).
  • the recent observations that exogenous phosphatidylcholine, but not lysophosphatidic acid, can reduce the activation of nuclear factor kappa-B and also expression of TNF-alpha induced genes in intestinal cells suggests a mechanism by which phosphatidylcholine preparations exert their therapeutic effect in ulcerative colitis patients.
  • DGAT1 inhibition can redirect incorporation of exogenous fatty acids from the intracellular triglyceride pool to the intracellular phosphatidylcholine pool, with potential therapeutic effects in ulcerative colitis.
  • Increasing transport of cholesterol from peripheral tissues to the bile for excretion requires high density lipoprotein (HDL).
  • HDL is secreted initially in a nascent or discoid form that acquires apolipoprotein A-1 and then accepts cholesterol from the other plasma lipoproteins.
  • the discoid form is a phospholipid membrane containing phosphatidylcholine, among other phospholipids.
  • a DGAT1 mediated increase in the availability of phosphatidylcholine in an organ that produces nascent HDL could improve reverse cholesterol transport in patients with atherosclerosis.
  • the present invention contemplates DGAT1 inhibitors as a compound present in a pharmaceutical composition.
  • DGAT1 inhibitors as a compound present in a pharmaceutical composition.
  • a prodrug derivative and a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
  • DGAT1 compounds Listed below are definitions of various terms used to describe the DGAT1 compounds. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group, e.g., wherein an attachment point of a certain group is limited to a specific atom within that group.
  • substituted or unsubstituted alkyl refers to straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-10 carbon atoms, containing 0 to 3 substituents.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl and the like.
  • Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy, alkanoyloxy, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfamoyl, sulfonamido, carbamoyl, cyano, carboxy, acyl, aryl, alkenyl, alkynyl, aralkyl, aralkanoyl, aralkylthio, arylsulfonyl, arylthio, aroyl, aroyloxy, aryloxycarbonyl, aralkoxy, guanidino, optionally substituted amino, heterocyclyl.
  • lower alkyl refers to those alkyl groups as described above having 1-7, preferably 2-4 carbon atoms.
  • halogen or “halo” refers to fluorine, chlorine, bromine and iodine.
  • alkenyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkynyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkylene refers to a straight-chain bridge of 4-6 carbon atoms connected by single bonds, e.g., -(CH 2 )X-, wherein x is 4-6, which may be interrupted with one or more heteroatoms selected from O, S, S(O), S(O) 2 or NR, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and the like; and the alkylene may further be substituted with one or more substituents selected from optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.
  • cycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may contain one or more carbon to carbon double bonds, or the cycloalkyl may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.
  • substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy
  • carboxamide refers to -C(O)-NHR , wherein R is selected from hydrogen, a C 1 -C 8 alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclyl group, and carboxamide is preferably -C(O)- NH 2 .
  • Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6- trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • alkoxy refers to alkyl-O-.
  • alkanoyl refers to alkyl-C(O)-.
  • alkanoyloxy refers to alkyl-C(O)-O-.
  • alkylamino and dialkylamino refer to alkyl-NH- and (alkyl) 2 N-, respectively.
  • alkanoylamino refers to alkyl-C(O)-NH- .
  • alkylthio refers to alkyl-S-.
  • alkylthiono refers to alkyl-S(O)-.
  • alkylsulfonyl refers to alkyl-S(O) 2 -.
  • alkoxycarbonyl refers to alkyl-O- C(O)-.
  • alkoxycarbonyloxy refers to alkyl-O-C(O)O-.
  • carbamoyl refers to H 2 NC(O)-, alkyl-NHC(O)-, (alkyl) 2 NC(O)-, aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl(aralkyl)-NC(O)- and the like.
  • sulfamoyl refers to H 2 NS(O) 2 -, alkyl-NHS(O) 2 -, (alkyl) 2 NS(O) 2 -, aryl-NHS(O) 2 , alkyl(aryl)-NS(O) 2 -, (aryl) 2 NS(O) 2 -, heteroaryl-NHS(O) 2 -, aralkyl-NHS(O) 2 -, heteroaralkyl- NHS(O) 2 - and the like.
  • sulfonamido refers to alkyl-S(O) 2 -NH-, aryl-S(O) 2 -NH-, aralkyl-S(O) 2 -NH-, heteroaryl-S(O) 2 -NH-, heteroaralkyl-S(O) 2 -NH-, alkyl-S(O) 2 -N(alkyl)-, aryl-S(O) 2 -N(alkyl)-, aralkyl-S(O) 2 -N(alkyl)-, heteroaryl-S(O) 2 -N(alkyl)-, heteroaralkyl-S(O) 2 -N(alkyl)- and the like.
  • sulfonyl refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
  • optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted by a substituent such as alkyl, acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.
  • the term “monocyclic aryl” refers to optionally substituted phenyl as described under aryl.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • aralkanoyl refers to aralkyl-C(O)-.
  • aralkylthio refers to aralkyl-S-.
  • aralkoxy refers to an aryl group bonded directly through an alkoxy group.
  • arylsulfonyl refers to aryl-S(O) 2 -.
  • arylthio refers to aryl-S-.
  • aroyl refers to aryl-C(O)-.
  • aroyloxy refers to aryl-C(O)-O-.
  • aroylamino refers to aryl-C(O)-NH-.
  • aryloxycarbonyl refers to aryl-O- C(O)-.
  • heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
  • the heterocyclic group may be attached at a heteroatom or a carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4- piperidonyl, pyridyl, pyridyl N-oxide,
  • bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyr
  • Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.
  • heterocyclyl includes substituted heterocyclic groups.
  • Substituted heterocyclic groups refer to heterocyclic groups substituted with 1 , 2 or 3 substituents.
  • heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
  • saturated or unsaturated heterocycloalkyl or “heterocycloalkyl” refers to nonaromatic heterocyclic or heterocyclyl groups as described above.
  • heteroaryl refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
  • heteroarylsulfonyl refers to heteroaryl-S(O)2-.
  • heteroaroyl refers to heteroaryl-C(O)-.
  • heteroaroylamino refers to heteroaryl-C(O)NH-.
  • heteroarylkyl refers to a heteroaryl group bonded through an alkyl group.
  • heteroarylkanoyl refers to heteroaralkyl-C(O)-.
  • heteroaryoaralkanoylamino refers to heteroaralkyl-C(O)NH-.
  • acyl refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.
  • acylamino refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.
  • divalent refers to a residue linked to at least two residues and optionally having further substituents.
  • substituted or unsubstituted divalent phenyl residue is considered to be equivalent to the expression “substituted or unsubstituted phenylene residue”.
  • WO 2007/126957 discloses a DGAT1 inhibitor compound having the following structure
  • A is a substituted or unsubstituted alkyl, cycloalkyl, aryl, or heterocyclyl group
  • L1 is selected from the group consisting of:
  • B is a substituted or unsubstituted, monocyclic, 5- or 6-membered divalent heteroaryl group
  • C-D is selected from the following cyclic structures:
  • C is a substituted or unsubstituted divalent phenyl group
  • D is a substituted or unsubstituted divalent non-aromatic monocyclic ring which is selected from a saturated or unsaturated divalent cycloalkyl group or a saturated or unsaturated divalent heterocycloalkyl group
  • the first cyclic component is a benzo-fused cyclic component wherein the ring which is fused to the phenyl part is a 5- or 6- membered ring, optionally comprising one or more heteroatoms, the first cyclic component being attached to the moiety B via its phenyl part, and
  • the second cyclic component is a cycloalkyl or cycloalkylidenyl residue which is attached to L2,
  • L2 is selected from the group consisting of:
  • E is selected from the group consisting of:
  • L2 is not a single bond or a divalent alkyl group if the moiety D is a single bond
  • L2 is not a single bond if the moiety D is an unsubstituted divalent phenyl group and E is a carboxylic acid or a derivative thereof,
  • E is not a carboxamide group if L2 comprises an amide group
  • E is not a -COOH group if D is a single bond and L2 is a -N(CH 3 )-C(O)- group wherein the carbonyl carbon atom is attached to the moiety E,
  • L2 is not a divalent N-methyl piperidinyl group if the moiety E is a pyridinyl- 1 ,2,4-triazolyl group,
  • L2 is not -C(O)-[R 4 ] e -[R 5 ]r- when C is a substituted or unsubstituted divalent phenyl group and D is a single bond, or a pharmaceutically acceptable salt thereof,
  • WO 2007/126957 discloses the synthetic reaction schemes suitable for preparing such compounds. WO 2007/126957 specifically disclose the following compounds.
  • DGAT1 compounds are disclosed in International Patent Application PCT/US2007/081607 (WO 2008/048991 ).
  • the disclosed compounds have the following basic formula.
  • A is selected from a substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalky, substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyle, wherein A is linked to L1 via a carbon member of the ring when A is a ring,
  • L1 is selected from the group consisting of:
  • R 3 and R 3A are, independently from each other, hydrogen or lower alkyl, m, n and p are, independently from each other, zero or an integer from 1 to 2, m + m + p is between 0 and 6, and is preferably 0, 1 , 2 or 3
  • R 4 and R 4 - are, independently from each other, hydrogen, halogen, hydroxyl, lower alkoxy, lower alkoxycarbonyl, carboxy or lower alkyl, or R 4 and R 4 ' are joined together to form a spiro residue of the formula
  • - r and s are, independently from each other, zero or an integer from 1 to 3,
  • R 3 ' is hydrogen or lower alkyl
  • R 3 - is hydrogen, halogen, hydroxyl, alkoxy, or lower alkyl
  • R 4 - is hydrogen or lower alkyl
  • B is a substituted or unsubstituted divalent heteroaryl group selected from one of the groups below:
  • Xi and X 2 ' are independently selected from O, NH, NR 9 or S, wherein R 9 is selected from lower alkyl, lower alkylamino, lower alkoxyalkyl, lower hydroxyalkyl,
  • Xi', X2, X3 and X 4 are independently selected from N, or CH, - C is
  • Ri is selected from hydrogen, cyano, lower alkylsulfonylamino, alkanoylamino, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylamino, lower dialkylamino, and NO 2 ,
  • R'i, R 2 and R' 2 are independently selected from hydrogen, halogen, trifluoromethyl, aryloxy, lower alkyl, lower alkoxy, lower alkylamino, lower dialkylamino, and NO 2 , or
  • C may also be a substituted or unsubstituted bicyclic aryl or heteroaryl group
  • D is selected from hydrogen, halogen, hydroxyl, cyano, alkanoylamino, carboxy, carbamoyl, -0-L 2 -E, -S- L 2 -E', -C(O)-O- L 2 -E, -L 2 -E", and -NR 6 -L 2 -E',
  • L 2 is -(CH 2 ) H -(CR 5 R 5 O p -(CI-I 2 W- E is; alkyl, acyl, alkoxycarbonyl, phosphonic acid, phosphonate, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonyl, -SO 2 -OH, sulfamoyl, sulfonylcarbamoyl, sulfonyloxy, sulfonamido, -C(O)-O-R-PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and when n' + m' + p' is equal to zero, E is not sulfonyloxy or sulfonamido,
  • E' is; alkyl, acyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonylcarbamoyl, sulfonyl, -SO 2 -OH, sulfamoyl, sulfonamido, phosphonic acid, phosphonate, sulfonyloxy, -C(O)-O-R-PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and when n' + m' + p' is equal to zero, E' is not sulfamoyl, sulfonamido, phosphonic acid, phosphonate, or sulfonyloxy,
  • E is; alkyl, acyl, alkoxycarbonyl, phosphonic acid, phosphonate, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonyl, sulfamoyl, sulfonyloxy, sulfonamido, -SO 2 -OH, sulfonylcarbamoyl, -C(O)-O-R- PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, m', n' and p' are, independently from each other, an integer from O to 4, m' + n' + p' is between O and 12, and is preferably O, 1 , 2, 3 or 4, R 5 and R 5 - are, independently from each other, hydrogen, halogen, hydroxyl, lower alk
  • X' is NR x , O, S or CR x R x -
  • - r' and s' are, independently from each other, zero or an integer from 1 to 3,
  • R x is hydrogen or lower alkyl
  • R x ' is hydrogen, halogen, hydroxyl, alkoxy, or lower alkyl
  • R x - is hydrogen or lower alkyl; or a prodrug or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of DGAT especially DGAT1 associated disorders.
  • WO 2008/048991 discloses the synthetic reaction schemes suitable for preparing such compounds.
  • WO 2008/048991 specifically disclose the following compounds. [2-(2-Chloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester [2-(4-Methoxy-2-methyl-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester [2-(2,6-Dimethyl-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester [2-(2,4-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester [2-(2,3-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-carbamic acid ethyl ester N-[2-(2,6-Dichloro-phenyl)-3H
  • Trifluoro-methanesulfonic acid 4-[6-(3,4-dimethyl-phenylcarbamoyl)-1 H- benzoimidazol-2-yl]-3,5-dimethyl-phenyl ester
  • Methanesulfonic acid 4-[6-(3,4-dimethyl-phenylcarbamoyl)-1 H-benzoimidazol-2-yl]-3,5- dimethyl-phenyl ester
  • A is a substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, optionally substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl;
  • Q is a divalent or trivalent cycloalkyl, aryl, heterocycle or heteroaryl
  • B is a substituted or unsubstituted divalent heteroaryl group selected from one of the groups below:
  • Xi and X 2 ' are independently selected from O, NH, NR 9 or S, wherein R 9 is selected from lower alkyl, lower alkylamino, lower alkoxyalkyl, lower hydroxyalkyl,
  • Xi', X2, X3 and X 4 are independently selected from N, or CH, C is
  • Ri is selected from hydrogen, cyano, lower alkylsulfonylamino, alkanoylamino, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylamino, lower dialkylamino, and NO 2 ,
  • R'i, R 2 and R' 2 are independently selected from hydrogen, halogen, trifluoromethyl, aryloxy, lower alkyl, lower alkoxy, lower alkylamino, lower dialkylamino, and NO 2 , or
  • C may also be a substituted or unsubstituted bicyclic aryl or heteroaryl group
  • D is selected from hydrogen, halogen, hydroxyl, cyano, alkanoylamino, carboxy, carbamoyl, -0-L 2 -E, -S- L 2 -E', -C(O)-O- L 2 -E, -L 2 -E", and -NR 6 -L 2 -E',
  • E is alkyl, acyl, alkoxycarbonyl, phosphonic acid, phosphonate, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonyl, -SO 2 -OH, sulfamoyl, sulfonylcarbamoyl, sulfonyloxy, sulfonamido, -C(O)-O-R-PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and when n' + m' + p' is equal to zero, E is not sulfonyloxy or sulfonamido,
  • E' is alkyl, acyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonylcarbamoyl, sulfonyl, - SO 2 -OH, sulfamoyl, sulfonamido, phosphonic acid, phosphonate, sulfonyloxy, -C(O)-O-R-PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and when n' + m' + p' is equal to zero, E' is not sulfamoyl, sulfonamido, phosphonic acid, phosphonate, or sulfonyloxy,
  • E" is alkyl, acyl, alkoxycarbonyl, phosphonic acid, phosphonate, cycloalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbony, carboxy, carbamoyl, sulfonyl, sulfamoyl, sulfonyloxy, sulfonamido, -SO 2 -OH, sulfonylcarbamoyl, -C(O)-O-R- PRO, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, m', n' and p' are, independently from each other, an integer from O to 4, m' + n' + p' is between O and 12, preferably O, 1 , 2, 3 or 4,
  • R 5 and R 5 > are, independently from each other, hydrogen, halogen, hydroxyl, lower alkoxy, or lower alkyl, or R 5 and R 5 ' are joined together to form a spiro residue of the formula wherein
  • X' is NR x , O, S or CR x R x -
  • - r' and s' are, independently from each other, zero or an integer from 1 to 3,
  • R x is hydrogen or lower alkyl
  • R x ' is hydrogen, halogen, hydroxyl, alkoxy, or lower alkyl
  • R x - is hydrogen or lower alkyl; or a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • Oxidative cyclocondensation of 3,4-diamino-benzoic acid or its methyl ester with substituted benzaldehyde provides the benzimidazole core.
  • the reaction is carried out in the open air in oxidizing media, such as DMSO or nitrobenzene, preferably the former, in the presence of a catalyst such as Oxone, FeCI3, Sc(OTf)3/Cu(OTf)2, or Yb(OTf)3/Cu(OTf)2.
  • compounds 2 is converted to compounds 8 by amidation reactions with a variety of 1 ,2-aminoalcohols in the presence of coupling reagents such as, but not limited to, HATU or EDCI.
  • coupling reagents such as, but not limited to, HATU or EDCI.
  • Oxidation of the hydroxyl group in compounds 8 affords compounds 9, which undergo cyclocondensation to provide compounds 10.
  • Compounds 9 are alternatively obtained from compounds 3 by amidation reaction with a variety of aminoketones.
  • HPLC Method 10 4.6 mm x 5 cm lnersil C8-3 reverse phase, 3.0 m particle size running a gradient of 10-90% MeCN/water (5mM ammonium formate) over a period of 2 min at a flow rate of 4 mL/min at 50 0 C.
  • DAD-UV detection 220-600 nm.
  • Example 1-1 ⁇ -tS ⁇ -Chloro-phenyO-ti.S ⁇ loxadiazol ⁇ -yll ⁇ .e-dichloro-phenyO-I H- benzoimidazole.
  • N-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (US Patent 6,391 ,865) (14.0 g. 47.3 mmol) in THF (200 ml.) under nitrogen atmosphere at - 78 0 C was added slowly methyllithium/LiBr (44.1 ml. of a 1.5 M solution in Et 2 O, 66.2 mmol). After 5 min of stirring, sec-BuLi (47.3 ml. of a 1.4 M solution in cyclohexane, 66.2 mmol) was added slowly to the reaction solution at -78 0 C.
  • Oxone (420 mg, 0.683 mmol) was added to a mixture of 3-(4-formyl-3,5-dimethyl- phenyl)-2,2-dimethyl-propionic acid methyl ester (250 mg, 1.00 mmol) and 4-[5-(4- Methoxy-phenyl)-[1 ,3,4]oxadiazol-2-yl]-benzene-1 ,2-diamine (prepared as described in Example 1-59, 300 mg, 1.06 mmol) in DMF (8 ml.) and water (0.8 ml_), and the mixture was stirred at room temperature for 18 h. The mixture was partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried over Na2SO4, concentrated and chromatographed to give the title compound, m/z 511.3 (MH+).
  • protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
  • the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
  • the above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, RT or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
  • diluent preferably, such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents, respectively and/or inert atmospheres, at low temperatures, RT or elevated temperatures, preferably at or near the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • compounds of the invention are either obtained in the free form, or in a salt form thereof, preferably, in a pharmaceutically acceptable salt form thereof, or as a prodrug derivative thereof.
  • salts may be converted into salts with pharmaceutically acceptable bases.
  • Such salts include alkali metal salts, like sodium, lithium and potassium salts; alkaline earth metal salts, like calcium and magnesium salts; ammonium salts with organic bases, e.g., trimethylamine salts, diethylamine salts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts and N- methyl-D-glucamine salts; salts with amino acids like arginine, lysine and the like. Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol.
  • the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
  • Compounds of the invention may be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, e.g., with inorganic acids, such as mineral acids, e.g., sulfuric acid, phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (Ci-C 4 )-alkanecarboxylic acids which, e.g., are unsubstituted or substituted by halogen, e.g., acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic, lactic, malic, tartaric or citric acid, such as amino acids, e.g., aspartic or glutamic acid, or with organic sulfonic acids, such as (CrC 4 )- alkylsulfonic acids, e.g., methanedi
  • Prodrug derivatives of any compound of the invention are derivatives of said compounds which following administration release the parent compound in vivo via some chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • exemplary prodrug derivatives are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein.
  • ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)- lower alkyl esters, the -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art.
  • lower alkyl esters e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the -(amino,
  • prodrug derivatives In view of the close relationship between the free compounds, the prodrug derivatives and the compounds in the form of their salts, whenever a compound is referred to in this context, a prodrug derivative and a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds contemplated of the present invention may be employed for the treatment of ulcerative colitis or atherosclerosis mediated by DGAT1 activity.
  • the present invention provides methods of using a compound or composition of the invention to treat or prevent ulcerative colitis or atherosclerosis by inhibition of DGAT1.
  • the present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active DGAT1 inhibitor compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal; transdermal and parenteral administration to mammals, including man, for the treatment of ulcerative colitis or atherosclerosis mediated by DGAT1 activity.
  • the pharmacologically active compounds of the invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • Injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, preferably about 1-50%, of the active ingredient.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the present invention provides pharmaceutical compositions as described above for the treatment of ulcerative colitis or atherosclerosis mediated by DGAT1 activity.
  • compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics or hypolipidemic agents as described above.
  • another therapeutic agent preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics or hypolipidemic agents as described above.
  • the present invention further relates to use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of ulcerative colitis or atherosclerosis mediated by DGAT1 activity.
  • the present invention also relates to a pharmaceutical composition for use in ulcerative colitis or atherosclerosis mediated by DGAT1 activity comprising a DGAT1 inhibitor compound, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefore.
  • the present invention further provides a method for the prevention and/or treatment of ulcerative colitis or atherosclerosis mediated by DGAT 1 activity, which comprises administering a therapeutically effective amount of a DGAT inhibitor compound.
  • a unit dosage for a mammal of about 50-70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5-500 mg of the active ingredient.
  • the therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved.
  • the present invention provides a method as defined above comprising coadministration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound as defined in the claims and described above, or a pharmaceutically acceptable salt thereof, and a second drug substance, said second drug substance being an anti-diabetic, a hypolipidemic agent, an anti-obesity agent or an antihypertensive agent, e.g., as indicated above.
  • treatment embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of progression and palliative treatment.
  • the above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 ⁇ 2 molar and 10 ⁇ 9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 mg/kg and 1000 mg/kg, preferably between about 1 mg/kg and 100 mg/kg.
  • the activity of the DGAT1 inhibitor compound according to the invention may be assessed by the following methods or methods well-described in the art:
  • the enzyme preparation used in this assay is a membrane preparation from Sf9 cells overexpressing human (His) 6 DGAT1. During all steps samples were chilled to 4 0 C. Sf9 cells expressing human (His)eDGATI were thawed at RT and re-suspended at a 10:1 ratio (ml. buffer/g of cells) in 50 mM HEPES, 1x Complete Protease Inhibitor, pH 7.5. The re-suspended pellet was homogenized for 1 min using a Brinkman PT 10/35 homogenizer with a 20 mm generator. Cells were lysed using Avestin Emulsiflex (chilled to 4 0 C) at 10000-15000 psi.
  • Lysate was centrifuged at 100,000 x g for 1 h at 4 0 C. Supernatant was removed and pellets were re-suspended in 50 mM HEPES, 1x Complete Protease Inhibitor, pH 7.5 at 1/6 the volume of supernatant. Re-suspended pellets were pooled and homogenized with 10 strokes of a Glas-Col motor driven teflon pestle on setting 70. The protein concentration of the membrane preparation was quantified using BCA protein assay with 1 % SDS. The membrane preparation was aliquoted, frozen on dry ice, and stored at -8O 0 C.
  • Dry compounds are dissolved in the appropriate volume of DMSO to a final concentration of 10 mM. A 10-point, 3-fold dose response is used to evaluate compound potency. All dilutions are performed in DMSO in a Greiner 384-well microplate.
  • Plate(s) are sealed with super pierce strong plate sealer using the thermo-sealer.
  • Plate(s) are centrifuged at 162 x g (1000 rpm for GH-3.8 rotor) for 5 min using Beckman GS-6R tabletop centrifuge. Samples were analyzed by LC/MS/MS using a Waters 1525 ⁇ LC and Quattro Micro API MS. Where indicated, tripalmitolein was used as an internal standard to control for instrument variation.
  • the DGAT1 inhibitors were shown to possess inhibitory activity with IC50 values ranging from 0.001 uM to 100 uM.

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Abstract

La présente invention concerne un procédé d’accroissement de phosphatidyl-choline in vivo par l’inhibition de l’activité enzymatique de la DGAT1 pour traiter des maladies pouvant être provoquées ou exacerbées par une production inadéquate de phosphatidyl-choline, comprenant l’athérosclérose et la rectocolite hémorragique.
PCT/EP2009/052701 2008-03-10 2009-03-09 Procédé d’accroissement de phosphatidyl-choline des cellules par l’inhibition de la dgat1 WO2009112445A1 (fr)

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