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WO1996036230A1 - Modulateurs pour de nouveaux membres de la superfamille des recepteurs steroide/thyroide - Google Patents

Modulateurs pour de nouveaux membres de la superfamille des recepteurs steroide/thyroide Download PDF

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Publication number
WO1996036230A1
WO1996036230A1 PCT/US1996/003865 US9603865W WO9636230A1 WO 1996036230 A1 WO1996036230 A1 WO 1996036230A1 US 9603865 W US9603865 W US 9603865W WO 9636230 A1 WO9636230 A1 WO 9636230A1
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Prior art keywords
car
falls
hydrogen
range
lower alkyl
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PCT/US1996/003865
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English (en)
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Ronald M. Evans
Barry M. Forman
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The Salk Institute For Biological Studies
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Priority to AU54265/96A priority Critical patent/AU5426596A/en
Publication of WO1996036230A1 publication Critical patent/WO1996036230A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone

Definitions

  • the present invention relates to intracellular receptors, and modulators therefor.
  • the present invention relates to methods for the identification of compounds which function as modulators (or precursors thereof) for specific members of the intracellular receptor family.
  • the present invention relates to various uses for the compounds so identified.
  • HREs hormone response elements
  • modulators for orphan member(s) of the steroid/thyroid superfamily of receptors which is related to the previously described constitutively active receptor- alpha (CAR- ⁇ ; also known as "MB-67,” see Baes et al., in Mol. and Cell. Biology 11:1544-1552 (1994)).
  • CAR- ⁇ constitutively active receptor- alpha
  • MB-67 constitutively active receptor- alpha
  • Compounds discovered in accordance with the present invention can be employed in a variety of applications, e.g., for the modulation of processes mediated by an isoform of CAR or CAR-like species, to increase the libido of a subject (especially a subject undergoing therapy using a 5 ⁇ -reductase inhibitor) , in a screening assay for the presence of receptors involved in the modulation of libido, and the like.
  • Also provided in accordance with the present invention are methods for the identification of compounds which modulate processes mediated by an isoform of CAR or
  • Figure 1 illustrates the suppression of an isoform of CAR by 5 -androstane derivatives.
  • R 2 is ⁇ -OR, wherein R is selected from hydrogen, lower alkyl, acyl or trimethylsilyl;
  • R 3 and R4 are each independently hydrogen or lower alkyl
  • X, Y, Z and A are each independently selected from hydroxy, alkoxy (of a lower alkyl group) , mercapto (of a lower alkyl group) , halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl, or sulfonamide; a falls in the range of 0 up to 4; b falls in the range of 0 up to 4; c falls in the range of 0 up to 4; and d falls in the range of 0 up to 3.
  • CAR or CAR-like isoform refers to a member of the steroid/thyroid superfamily of receptors which is optionally constitutively active, and has at least 75 % overall amino acid identity (up to 86 % sequence similarity) with the receptor set forth in SEQ ID N0:1 (CAR- ⁇ ) , at least 88 % amino acid identity (up to 91 % sequence similarity) in the DNA binding domain thereof, with respect to the DNA binding domain of the receptor set forth in SEQ ID N0:1, and at least 74 % amino acid identity (up to 87 % sequence similarity) in the ligand binding domain thereof, with respect to the ligand binding domain of the receptor set forth in SEQ ID N0:1.
  • the phrase "modulating the activity of a CAR or CAR-like isoform” refers to the ability of a modulator (e.g., a ligand or precursor thereof) for an isoform of CAR or a CAR-like species to induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • a modulator e.g., a ligand or precursor thereof
  • processes mediated by an isoform of CAR or a CAR-like species refers to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to natural or synthetic androstans. Modulation of such processes can be accomplished in vitro or in vivo . In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
  • lower alkyl refers to straight or branched chain alkyl groups having in the range of about 1 up to 4 carbon atoms
  • alkyl refers to straight or branched chain alkyl groups having in the range of about 1 up to 12 carbon atoms
  • substituted alkyl refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy (of a lower alkyl group) , mercapto (of a lower alkyl group) , aryl, carboxyl, heterocyclic, halogen, trifluoro ethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, and the like.
  • acyl refers to alkyl- carbonyl groups.
  • a CAR or CAR-like isoform comprising: contacting host cell(s) containing receptor- encoded DNA and a suitable hormone response element linked to reporter-encoded DNA with test compound, and determining the effect of test compound on the level of expression of said reporter.
  • the receptor-encoded DNA employed in the practice of the present invention will also encode one or more exogenous transactivation domains, such as, for example, the T. or ⁇ 2 transactivation domains described in United States Patent No. 5,217,867, which is incorporated by reference herein in its entirety.
  • Identification methods involve the use of a functional bioassay system, wherein the CAR or CAR-like isoform (as defined herein) and a reporter plasmid are cultured in suitable host cells in the presence of test compound. Evidence of transcription (e.g., expression) of reporter gene is then monitored to determine the presence of an activated receptor-ligand complex.
  • the functional bioassay system utilizes two plasmids: an "expression" plasmid and a "reporter" plasmid.
  • the expression plasmid can be any plasmid which contains and is capable of expressing DNA encoding the CAR or CAR-like isoform receptor protein, in a suitable host cell.
  • the reporter plasmid can be any plasmid which contains an operative hormone response element functionally linked to an operative reporter gene.
  • Exemplary reporter genes include chloramphenicol transferase (CAT) , luciferase (LUC) , beta-galactosidase (?-gal) , and the like.
  • Exemplary promoters include the simian virus (SV) promoter or modified form thereof (e.g., ⁇ SV) , the thymidine kinase (TK) promoter, the mammary tumor virus (MTV) promoter or modified form thereof (e.g., ⁇ MTV) , and the like [see, for example, Mangelsdorf et al., in Nature _34_5:224-229 (1990), Mangelsdorf et al., in Cell 6.6:555-561 (1991), and Berger et al., in J.
  • SV simian virus
  • TK thymidine kinase
  • MTV mammary tumor virus
  • the plasmids pGMCAT, pGHCAT, and the like are examples of reporter plasmids which contain an operative hormone responsive promoter/enhancer element functionally linked to an operative reporter gene, and can therefore be used in the above-described functional bioassay (see Example 1 for details on the preparation of these plasmids) .
  • the operative hormone responsive promoter/enhancer element is the MTV LTR; in pGHCAT it is the functional portion of the growth hormone promoter.
  • the operative reporter gene is the bacterial gene for chloramphenicol acetyltransferase (CAT) .
  • operative response element functionally linked to an operative reporter gene
  • the word “operative” means that the respective DNA sequences (represented by the terms “hormone response element” and “reporter gene”) are operational, i.e., work for their intended purposes; the word “functionally” means that after the two segments are linked, upon appropriate activation by a ligand-receptor complex, the reporter gene will be expressed as the result of the fact that the "hormone response element” was "turned on” or otherwise activated.
  • the expression plasmid and the reporter plasmid are co-transfected into suitable host cells.
  • the transfected host cells are then cultured in the presence and absence of a test compound to determine if the test compound is able to produce activation of the promoter operatively linked to the hormone response element of the reporter plasmid. Thereafter, the transfected and cultured host cells are monitored for induction (i.e., the presence) of the product of the reporter gene sequence.
  • Cells contemplated for use in the practice of the present invention include transformed cells, non- transformed cells, neoplastic cells, primary cultures of different cell types, and the like.
  • Exemplary cells which can be employed in the practice of the present invention include liver cell lines (e.g., Hep-G2) , primary hepatocytes, adipocyte or pre-adipocyte cell lines (e.g., 3T3-L1 cells, 3T3-442-A cells, OB17 cells, and the like) , as well as CV-1 cells, HuTu ⁇ O cells, F9 cells, NTERA2 cells, NB4 cells, HL-60 cells, 293 cells, Hela cells, NIH-3T3 cells, and the like.
  • liver cell lines e.g., Hep-G2
  • primary hepatocytes e.g., primary hepatocytes
  • adipocyte or pre-adipocyte cell lines e.g., 3T3-L1 cells, 3T3-442-A cells,
  • COS-1 referred to as COS
  • COS cells are monkey kidney cells that express SV40 T antigen (Tag)
  • CV-1 cells do not express SV40 Tag.
  • Tag SV40 T antigen
  • the presence of Tag in the COS-1 derivative lines allows the introduced expression plasmid to replicate and provides a relative increase in the amount of receptor produced during the assay period.
  • CV-1 cells are presently preferred because they are particularly convenient for gene transfer studies and provide a sensitive and well-described host cell system.
  • physiological conditions are readily understood by those of skill in the art to comprise an isotonic, aqueous nutrient medium at a temperature of about 37°C.
  • a method to increase the libido of a subject comprising inhibiting the activity of CAR or CAR-like isoforms (as defined above) .
  • the above-described method to increase libido can be carried out by administering to a subject a libido-enhancing amount of a steroid-like compound having the structure I, as described herein.
  • physiologically active composition(s) comprising a compound having the structure I, as described herein, in a suitable vehicle rendering said compound amenable to oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, nasal delivery, and the like.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active compound i.e., compounds of structure I as described herein
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl onostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid) , naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc. , or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • compositions contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug. Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug. Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, it is up to the practitioner to determine a subject's response to treatment and
  • Typical daily doses lie within the range of from about 0.5 ⁇ g to about 10 mg per kg body weight, and, preferably within the range of from 50 ⁇ g to 1 mg per kg body weight and can be administered up to four times daily.
  • the daily IV dose lies within the range of from about 1 ⁇ g to about 10 mg per kg body weight, and, preferably, within the range of from 10 ⁇ g to 500 ⁇ g per kg body weight.
  • compositions useful for ameliorating the libido-reducing effects of a 5 ⁇ -reductase inhibitor comprise a libido-enhancing amount of a steroid-like compound having the structure I, as described herein, and a 5 ⁇ -reductase inhibitor.
  • 5 ⁇ -reductase inhibitors suitable for use in the practice of the present invention are finasteride (PROSCAR) .
  • a method for ameliorating the libido-reducing effects of a 5 ⁇ -reductase inhibitor comprising co-administering, to a subject being treated with 5 ⁇ -reductase inhibitor(s) , a libido-enhancing amount of a steroid-like compound having the structure I, as described herein.
  • a method of screening cells or cell extracts to determine the presence of receptors involved in the modulation of libido comprising
  • TK-LUC The MTV-LTR promoter sequence is removed from the MTV-LUC plasmid described by Hollenberg and Evans in Cell 55:899-906 (1988) by tfindlll and Xhol digest, and cloned with the Hindlll-X ol fragment of the Herpes simplex virus thymidine kinase gene promoter (-105 to +51 with respect to the transcription start site, m, isolated from plasmid pBLCAT2, described by Luckow & Schutz in Nucleic Acids Res. 33:5490 (1987)) to generate parental construct TK-LUC.
  • pTK- ⁇ RARE The MTV-LTR promoter sequence is removed from the MTV-LUC plasmid described by Hollenberg and Evans in Cell 55:899-906 (1988) by tfindlll and Xhol digest, and cloned with the Hindlll-X ol fragment of the Herpes simplex virus thymidine kinase
  • 2 j -LUC One, two or three copies of double-stranded beta-retinoic acid response element ( ⁇ RKRE) oligonucleotides, comprising a direct repeat of two half sites separated by a spacer of five nucleotides, wherein each half site comprises the sequence
  • R is selected from A or G; B is selected from G, C, or T; each N is independently selected from
  • M is selected from A or C; and x falls in the range of 0 up to 5; with the proviso that at least 4 nucleotides of said -RGBNNM- sequence are identical with the nucleotides at corresponding positions of the sequence -AGGTCA-, is cloned upstream of the TK promoter of TK-LUC at the Hindlll site.
  • response elements having a similar structure to that set forth above, except having a spacer of only four nucleotides, can be used.
  • response elements comprising a direct repeat of two half sites separated by a spacer of four nucleotides, wherein each half site comprises the sequence N ⁇ -RGBNNM-, as described above, can be used in place of the ⁇ RARE described above.
  • CMX-?GAL The coding sequence for the E. coli ?-galactosidase gene is isolated from plasmid pCHllO [see Hall et al., J. Mol. Appl. Genet. 2:101-109 (1983)] by i ⁇ indlll and BamEI digest, and cloned into pCMX eucaryotic expression vector [see Umesono et al., supra] . 15
  • nucleic acid residues 303 to 545 of SEQ ID N0:1 is prepared by PCR.
  • the probe is labeled by the random-primer labeling method or by PCR using 32P nucleotides.
  • the labeled probe is then used to probe a lambda-gtll mammalian liver cDNA library (e.g., mouse liver cDNA library or other readily available library, such as are commercially available from Clontech or Stratagene) to identify related receptors.
  • the filters are autoradiographed for 3 days at -70°C using an intensifying screen.
  • sequence analysis of at least one of the positive clones indicates that this clone encodes a novel member of the steroid/thyroid superfamily of receptors, having approximately 75 % overall amino acid identity with the receptor set forth in SEQ ID N0:1, approximately 88 % amino acid identity in the DNA binding domain thereof, with respect to the DNA binding domain of the receptor set forth in SEQ ID N0:1, and approximately 74 % amino acid identity in the ligand binding domain thereof, with respect to the ligand binding domain of the receptor set forth in SEQ ID N0:1.
  • Hybridization conditions for such rescreening comprise a hybridization mixture containing 50% formamide, IX Denhart's, 5X SSPE, 0.1% SDS, 100 ⁇ g/ml denatured salmon sperm DNA and 10 cpm of [ 32 P]-labelled probe.
  • the filters are autoradiographed for 3 days at -70°C using an intensifying screen.
  • a lambda-gtll mammalian liver cDNA library is screened in duplicate with a 32P-labeled synthetic oligonucleotide:
  • TGYGARGGNT GYAARGGNTC TTT (SEQ ID NO:3), under low-stringency conditions (i.e., 1M NaCl/0.05mM Tris-HCl, pH 8.0/5mM EDTA/150 units of heparin per ml/0.05%, sodium pyrophosphate/100 ⁇ g of yeast RNA per ml/0.1% (wt/vol) NaDodS0 4 at 46°C) and washed at high stringency, as described by Burglin et al., in Nature 241:239-243 (1989).
  • Y is selected from C or T
  • R is selected from A or G
  • N is any one of A, G, C or T.
  • the oligonucleotide employed is a mixture of all possible DNA sequences encoding the amino acid sequence: CEGCKGFF (SEQ ID NO:4), wherein each letter above is the conventional single letter abbreviation for amino acid residues, i.e., C is cysteine,
  • E glutamic acid
  • G glycine
  • K lysine
  • F phenylalanine
  • CV-1 cells are co-transfected with a vector encoding the CAR isoform isolated as described in Example 2 (incorporated into a CMV-driven expression vector) , and pTK-?RARE-LUC at a ratio of about 100 ng of receptor- encoding DNA per 10 cells.
  • the usual amounts of DNA per 10 5 cells are 100 ng of CDM8-CAR, 300 ng of pTK-ffRARE-LUC, and 500 ng of CMX-?GAL.
  • transfections are performed in triplicate. The plates are then incubated for 2-3 hours at 37°C.
  • the cells are washed with fresh medium. Fresh medium containing one concentration of a serial dilution of agonist is added to each well. A typical agonist dilution series extends from 10 -5M through 10-11M. A solvent control is performed for each agonist. The cells are incubated at 37°C for 1-2 days.
  • the cells are rinsed twice with buffered saline solution. Subsequently, cells are lysed, in situ , by adding 200 ⁇ l of lysis buffer. After 30 minutes incubation at room temperature, 40 ⁇ l aliquots of cell lysate are transferred to 96-well plates for luciferase reporter gene assays and -galactosidase transfection controls [see Heyman et al.. Cell 8:397-406 (1992)].
  • the data are expressed as relative light units
  • RLUs per O.D. unit of ?-galactosidase per minute.
  • the triplicates are averaged for each concentration and plotted as normalized RLUs against the dose of agonist or as fold induction vs the dose of agonist.
  • the results of testing with a variety of different compounds are presented in the following table:
  • the selectivity of a modulator for a particular receptor can be measured by comparing the activation/repression of that receptor with the activation/repression of some other related receptor with the same modulator.
  • Effector plasmid, reporter plasmid, and yff-galactosidase control plasmid are co-transfected into CV-1 cells at a ratio of about 1:3:5, using a liposome- mediated method, employing N- ⁇ l-(2,3-dioleoyloxy)propyl- N,N,N-trimethy1 ammonium methyl sulfate ⁇ (i.e., D0TAP (Boehringer Manheim) according to manufacturer's instructions in Dulbecco's modified Eagle's medium (DMEM) with 10% delipidated hormone-depleted fetal calf serum.
  • D0TAP Dulbecco's modified Eagle's medium
  • the cells are washed twice with fresh DMEM and test compound is added to the media to the final molar concentration indicated in Figure 1. After 24-48 hours of incubation, the media is removed and the cells are lysed. Aliquots are assayed for luciferase and yff-galactosidase activity. Luciferase activity is normalized to optical density units of y ⁇ -galactosidase per minute of incubation.
  • ADDRESSEE Pretty, Schroeder, Brueggemann & Clark
  • AGC AAA AGC ATT GGT CCC ACC TGC CCC TTT GCT GGA
  • AGC TGT GAA GTC 437 Ser Lys Ser lie Gly Pro Thr Cys Pro Phe Ala Gly Ser Cys Glu Val 40 45 50 55
  • ATC AAG GGC CAG CAG CGA AGG CCC CGG GAT CGG TTT CTG TAT GCG
  • AAG 1205 lie Lys Gly Gin Gin Gin Arg Arg Pro Arg Asp Arg Phe Leu Tyr Ala Lys 300 305 310
  • MOLECULE TYPE DNA (genomic)

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Abstract

L'invention concerne des modulateurs pour un ou plusieurs membres orphelins de la superfamille des récepteurs de type stéroïde/thyroïde, en liaison avec le récepteur constitutivement actif alpha (CAR-alpha) décrit antérieurement. On a identifié des composés de la catégorie générale des androstans, agissant comme modulateurs pour une isoforme de CAR récemment découverte. Les composés décrits dans la présente invention peuvent être utilisés dans diverses applications, à savoir, par exemple, la modulation des processus dont la médiation est assurée par une isoforme de CAR ou de types assimilés au CAR, augmentation de la libido chez un sujet (notamment ceux qui subissent une thérapie à base d'inhibiteur de réductase 5-α), dans une méthode de criblage visant à déceler la présence de récepteurs intervenant dans la modulation de la libido, etc. On décrit par ailleurs des procédés qui permettent d'identifier les composés modulant des processus dont la médiation est assurée par une isoforme de CAR ou de types assimilés au CAR, ainsi que des compositions nouvelles dérivées de ces composés.
PCT/US1996/003865 1995-05-16 1996-04-17 Modulateurs pour de nouveaux membres de la superfamille des recepteurs steroide/thyroide WO1996036230A1 (fr)

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