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WO2000010589A1 - Analogues de la somatostatine - Google Patents

Analogues de la somatostatine Download PDF

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Publication number
WO2000010589A1
WO2000010589A1 PCT/US1999/019090 US9919090W WO0010589A1 WO 2000010589 A1 WO2000010589 A1 WO 2000010589A1 US 9919090 W US9919090 W US 9919090W WO 0010589 A1 WO0010589 A1 WO 0010589A1
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WO
WIPO (PCT)
Prior art keywords
cys
tyr
lys
thr
isocyanate
Prior art date
Application number
PCT/US1999/019090
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English (en)
Other versions
WO2000010589A9 (fr
Inventor
Jeffrey D. White
Original Assignee
White Jeffrey D
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by White Jeffrey D filed Critical White Jeffrey D
Priority to AU63829/99A priority Critical patent/AU6382999A/en
Publication of WO2000010589A1 publication Critical patent/WO2000010589A1/fr
Publication of WO2000010589A9 publication Critical patent/WO2000010589A9/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Somatostatin is a cyclic tetradecapeptide which inhibits release of several
  • intestinal peptide secretin, cholecystokinin, bombesin, gastrin releasing peptide, gastrin,
  • thyroid releasing hormone thyroid releasing hormone
  • pancreatic polypeptide e.g., interleukins
  • growth factors e.g., epidermal growth factor, nerve growth factor
  • growth factors e.g., epidermal growth factor, nerve growth factor
  • vasoactive amines e.g., serotonin
  • analogues have been prepared in order to enhance the duration of effect, biological
  • the present invention provides novel chemically modified somatostatin analogs
  • the present invention provides a somatostatin analog which
  • Figure 1 is a graph which illustrates that peptide 3502 suppresses secretion of
  • FIG. 1 is a graph which shows that orally administered peptide 3502 prevents
  • the compounds of this invention are cyclic heptapeptide analogs of somatostatin
  • RI is C1-C4 alkyl, adamantyl,
  • Preferred compounds of this invention include compounds of Formula I:
  • RI is C1-C4 alkyl, adamantyl,
  • Y is a bond, C1-C4 alkenyl, CO, or SO 2 ;
  • X ! and X 2 are independently, flourine, chlorine, bromine, iodine, C1-C4 alkyl,
  • Y is CH 2
  • X is hydrogen
  • Rl is C1-C4 alkyl, adamantyl,
  • X ] and X 2 are independently, flourine, chlorine, bromine, iodine, C1-C4 alkyl, 0 II
  • Another preferred somatostatin analog of this invention is a compound of
  • X is hydrogen
  • Y is a bond
  • the invention features compounds, compositions and methods for the treatment
  • somatostatin or factors which can be regulated by somatostatin, including but not limited to growth
  • the compounds can be administered in the dosages used for somatostatin or,
  • cancer particularly growth hormone- or growth factor-
  • the compounds can also be used in the management of diabetes
  • Alzheimer's disease can also be used to treat Alzheimer's disease and as gastric cytoprotective compounds for
  • ulcer therapy The compounds will also be useful in treating diabetes-related conditions.
  • compounds may be related to their ability to antagonize the actions of cancer-related
  • growth factors such as epidermal growth factor, insulin-like growth factor (IGF-1), or others.
  • VEGF vasoactive endothelial growth factor
  • salts of the somatostatin analogs are inorganic acids, such as hydrochloric acid, sulfuric
  • organic salts or hydroxides such as Ca and Zn salts or the addition polymeric organic
  • a pharmaceutically acceptable carrier substance e.g., magnesium carbonate, lactose,
  • a phospholipid or mannitol to form a pharmaceutical composition.
  • composition can also be administered as an ointment, gel, cream or lotion for application to the skin, or as a solution capable of being administered intravenously,
  • the therapeutic composition can be any suitable therapeutic composition.
  • compositions or methods of administration of the somatostatin analogs are provided.
  • R is C1-C4 alkyl, adamantyl,
  • X, and X 2 are independently, fluorine, chlorine, bromine, iodine, C1-C4 alkyl, NO 2 or
  • somatostatin receptors hsstl, hsst2, hsst3, hsst4, hsst5 have been identified and cloned.
  • Somatostatin receptor subtype 2 is
  • CHO-Kl cells were grown as monolayers in Dulbecco's Modified Eagle's medium (DMEM, Mediatech, Washington DC) supplemented with 10% fetal calf serum, non-essential amino acids, 2mM glutamine, lmM pyruvate and 500 mg/mL gentamycin in 5% CO2 at 37°C.
  • DMEM Dulbecco's Modified Eagle's medium
  • hsst expression of hsst in CHO-Kl cells.
  • CHO-Kl cell lines stably expressing hsst were created and propagated.
  • the predicted coding region of each hsst was generated by PCR from human genomic DNA and ohgonucleotides corresponding to the coding region 5' and 3' ends as primers.
  • the DNA fragment generated by PCR contained a Hind III restriction site at the 5' end and a Not 1 restriction site at the 3' end.
  • the fragment was digested with these two restriction enzymes and directionally subcloned into the Hind Ill/Not 1 sites of the mammalian expression vector pCDNAl. The identity of each insert was verified by DNA sequencing.
  • the construct was co-transfected with pSV2neo into a CHO-Kl cell line using the calcium phosphate protocol. Stable transfectants were selected using 400 mg/mL G418 and maintained in supplemented DMEM. After an initial ligand binding screen, one stable clone for each sst was chosen for all subsequent experiments.
  • Preparation of Plasma Membranes CHO/sst cells grown on 100mm tissue culture dishes were washed with ice cold PBS then scraped into 5ml of 50mM HEPES, pH 7.4-5mM MgCl 2 - 200 KIU/mL aprotinin - 2mg/mL PMSF and 2 mg/mL bacitracin (homogenization buffer).
  • the cells were homogenized on ice using a Brinkman Polytron (setting 5, 15 sec) then re-homogenized with a hand held homogenizer (6 strokes). After centrifugation at 500 x g for 5 min. at 4°C, the supernatant was centrifuged again at 12,000 x g for 25 minutes at 4°C. The final pellet was resuspended in homogenization buffer. Protein content was measured using the bicinchoninic acid protein assay using BSA as a standard.
  • Ki was determined using software programs Ligand or
  • Table 1 lists the results of receptor binding studies for a
  • modified peptides were determined by evaluating their inhibitory potency on pituitary growth hormone (GH) release in sodium pentobarbital-anesthetized rats.
  • GH pituitary growth hormone
  • the pentobarbital treated rat is a well characterized and frequently used model for studying GH secretory dynamics (see K. Chihara, A. Armura and AV Schally 1979 Endocrinology 104 1434).
  • Dose-Response Studies Adult male Sprague-Dawley rats weighing 250-300g with jugular vein cannulas were obtained from Zivic-Miller Labs, Zelienople, PA.
  • the rats were anesthetized with sodium pentobarbital (60mg/kg of body weight, administered i.p.). Thirty minutes later, the animals were injected iv. with saline or test compound at doses ranging from 0.1 to 30 ⁇ g/kg. Blood samples (250 ⁇ L) were drawn from the jugular vein cannula 10 min prior to test compound injection (baseline) and 5, 15, 30, 45 and 60 minutes after injection. The plasma was separated and assayed for GH by RIA using material supplied by the National Hormone and Pituitary Program, and for glucagon and glucose using commercially available reagents.
  • Figure 1 illustrates the dose response of peptide 3502 at three dosage levels 5 ⁇ g/kg, 2.5 ⁇ g/kg, and 1 ⁇ g/kg. At each dosage, the peptide was shown to be effective in suppressing production of growth hormone.
  • Time-Course Assay Groups of cannulated rats were treated with sodium pentobarbital as in the dose-response assay. Thirty minutes later animals were injected via the jugular cannula with saline or test compound at the minimum dose giving maximal GH inhibition. Sodium pentobarbital at half the initial dose was given at 60- to 90-minute intervals to maintain anesthesia. Blood (250 ⁇ L) was collected from the jugular vein at approximately 15, 30, 60, 120, 180, and 240 min. after the injection of test compound and treated as described above. Data from the time-course assay are shown in Table 2.
  • Oral activity Adult male Sprague-Dawley rats weighing 250-300g with jugular vein and
  • gastric cannulas were obtained from Zivic-Miller Labs, Zelienople, PA. On the evening
  • rats Prior to assay, rats were given 5 gram of food to eat with free access to water. On the day
  • the rats were anesthetized with sodium pentobarbital (60mg/kg of body weight,
  • the graph representing peptide 3502 shows that the peptide, orally

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des analogues de la somatostatine qui renferment une séquence d'heptapeptides chimiquement substitués dont les groupes cystéine sont situés aux emplacements 1 à 6 et qui sont reliés les uns aux autres pour former un pont bisulphure dans la configuration monocyclique. Des modifications d'ordre chimique sont apportées au groupe amino libre de cystéine du peptide (1). Il a été démontré que le peptide analogue de la somatostatine pouvait être modifié par adjonction d'isocyanates, d'isothiocyanates, de chlorures d'acide, de chloroformates et d'éthers de glycidyle (époxides) du groupe amino libre avec, au terminal cystéine, une amélioration marquée de l'aptitude des composés chimiquement modifiés à se lier à des récepteurs de la somatostatine.
PCT/US1999/019090 1998-08-24 1999-08-23 Analogues de la somatostatine WO2000010589A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63829/99A AU6382999A (en) 1998-08-24 1999-08-23 Somatostatin analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9756298P 1998-08-24 1998-08-24
US60/097,562 1998-08-24

Publications (2)

Publication Number Publication Date
WO2000010589A1 true WO2000010589A1 (fr) 2000-03-02
WO2000010589A9 WO2000010589A9 (fr) 2000-12-14

Family

ID=22264038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/019090 WO2000010589A1 (fr) 1998-08-24 1999-08-23 Analogues de la somatostatine

Country Status (2)

Country Link
AU (1) AU6382999A (fr)
WO (1) WO2000010589A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145337A (en) * 1977-10-11 1979-03-20 Hoffmann-La Roche Inc. Aminoethylglycine containing polypeptides
US5770687A (en) * 1995-06-07 1998-06-23 Peptor Limited Comformationally constrained backbone cyclized somatostatin analogs
US5846934A (en) * 1996-02-20 1998-12-08 American Cyanamid Company Pure somatostatin antagonist and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145337A (en) * 1977-10-11 1979-03-20 Hoffmann-La Roche Inc. Aminoethylglycine containing polypeptides
US5770687A (en) * 1995-06-07 1998-06-23 Peptor Limited Comformationally constrained backbone cyclized somatostatin analogs
US5846934A (en) * 1996-02-20 1998-12-08 American Cyanamid Company Pure somatostatin antagonist and methods of use thereof

Also Published As

Publication number Publication date
WO2000010589A9 (fr) 2000-12-14
AU6382999A (en) 2000-03-14

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