EP0996457A1 - Peptides liberateurs de f.s.h. - Google Patents

Peptides liberateurs de f.s.h.

Info

Publication number
EP0996457A1
EP0996457A1 EP98926280A EP98926280A EP0996457A1 EP 0996457 A1 EP0996457 A1 EP 0996457A1 EP 98926280 A EP98926280 A EP 98926280A EP 98926280 A EP98926280 A EP 98926280A EP 0996457 A1 EP0996457 A1 EP 0996457A1
Authority
EP
European Patent Office
Prior art keywords
peptide
seq
recited
xaa
animal
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98926280A
Other languages
German (de)
English (en)
Other versions
EP0996457A4 (fr
Inventor
Samuel M. Mccann
Wen H. Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Louisiana State University and Agricultural and Mechanical College
Original Assignee
Louisiana State University and Agricultural and Mechanical College
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 Louisiana State University and Agricultural and Mechanical College filed Critical Louisiana State University and Agricultural and Mechanical College
Publication of EP0996457A1 publication Critical patent/EP0996457A1/fr
Publication of EP0996457A4 publication Critical patent/EP0996457A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C12N15/8257—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits for the production of primary gene products, e.g. pharmaceutical products, interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • 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
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43563—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • This invention pertains to compositions and methods for selectively stimulating or inhibiting the release of follicle-stimulating hormone from the anterior lobe of the pituitary gland.
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • FSH is critical for spermatogenesis and for ovarian follicle development
  • LH is critical to androgen secretion in males, and estrogen secretion, ovulation, and formation of the corpus luteum in females.
  • a hormone with specific activity for releasing FSH but not LH could be used to increase fertility in humans or other animals, or to correct fertility problems caused by defective hypothalamic control of FSH secretion.
  • an FSH-specific releasing factor will inhibit FSH secretion, thereby inhibiting spermatogenesis in males, or inhibiting development of follicles and ovarian development in females, providing a new antifertility drug. It is also possible that very high doses of an FSH-specific releasing factor will inhibit FSH secretion, rather than stimulate it. Prior indirect evidence has suggested that separate factors could be responsible for triggering the release of FSH and for triggering the release of LH in mammals. However, this hypothesis could not previously be confirmed, because no previous work successfully isolated a potent factor that selectively induces the release of FSH, but not LH. See McCann, S.
  • Luteinizing hormone releasing hormone (LHRH, also known as gonadotropin-releasing hormone, or GnRH) has both LH-releasing activity and FSH-releasing activity. See Schally,
  • Gonadotropin-releasing hormone one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones, Science, 173:1036-1038, 1971; and D. Lincoln, Gonadotropin-releasing hormone (GnRH): basic physiology, pp. 218-229 in L. DeGroot et al., Endocrinology, 1995. The latter states at page 218: "There is no convincing evidence for the existence of a separate and specific FSH-releasing hormone, although some components of the GnRH precursor and some GnRH analogues appear to differ in the degree to which they stimulate the secretion of the two gonadotropins.”
  • Lamprey 1-LHRH-I has been reported to have relatively low activity in releasing either FSH or LH in rats. Yu, W. et ⁇ l., Selective FSH-releasing activity of comparison with gonadotropin-releasing abilities of analogs of GAP and natural LHRHs, Brain Res. Bull., 25:867-873, 1990.
  • Neurons that are immunopositive for 1-LHRH-I have been identified in human hypothalami. projecting from the arcuate region to the median eminence. Stopa, E. et al, Polygenic expression of gonadotropin-releasing hormone (GnRH) in human?, Peptides, 9:419- 423, 1988.
  • GnRH gonadotropin-releasing hormone
  • United States patent 4,973,577 discloses a 28,000 dalton protein isolated from porcine follicular fluid that stimulates the release of FSH, but not of LH. This protein has a relatively slow onset of action, and is relatively difficult to synthesize. The protein was said to be a homodimer of two chains of 116 amino acid residues each, or 232 residues total.
  • United States patent 3,888,836 discloses a method for synthesizing mammalian
  • LHRH Mammalian LHRH causes increased serum levels of both LH and FSH.
  • United States patent 4,721,775 discloses certain peptides that non-selectively induce the secretion of both LH and FSH.
  • FSH-RF FSH-releasing factor
  • LHRH's from various species are disclosed in Lumpkin et al., 1987.
  • One analog was found to have only FSH-releasing activity, but its potency was very low, and the slope of its dose- response curve was flat.
  • LHRH-II had slightly preferential FSH-releasing activity in vivo (unpublished data).
  • 1-LHRH-III is the long-sought FSH-releasing factor. This activity has been confirmed in vitro by incubation with hemi-anterior pituitaries of adult male rats. Following intravenous injection at the lowest dose tested to date (10 picomoles), this peptide produced an increase in FSH in vivo (P ⁇ 0.01) within ten minutes, but no significant increase in LH. Such a selective effect has not previously been reported for any analog of mammalian LHRH.
  • Lamprey III pGlu-His-Trp-Ser-His-Asp-Trp-Lvs- Pro-Gly-NH 2 (SEQ. ID NO. 1)
  • Rats Male and female Sprague-Dawley rats (Holtzmann, Madison, WI; 200-250 g) were housed two per cage under controlled conditions of temperature (23-25°C) and lighting (on from 0500 to 1700 hr). The animals had free access to a pellet diet and to tap water.
  • the 1-LHRH-III used in the experiments reported here was synthesized by standard solid-state peptide synthesis methods, and was purified to greater than 97% purity by preparative reverse-phase high performance liquid chromatography. All other peptides used were purchased from Peninsula Laboratories (Belmont, CA), except as otherwise noted.
  • AP anterior pituitary
  • the APs were incubated for 3 hr in fresh KRB buffer alone (control), or in KRB containing one of various concentrations of synthetic mammalian (m)-LHRH, 1-LHRHr III, 1-LHRH-I, chicken (c)-LHRH-II, or salmon (s)-LHRH.
  • the medium was then aspirated, and was stored frozen at -20°C until radio-immunoassays (RIA) for FSH and LH were conducted.
  • FSH and LH were measured using kits supplied by the National Institute of Arthritis Digestive Diabetes and Kidney Disease; hormone values were expressed in terms of
  • estradiol benzoate Sigma Chemical Co., St. Louis, MO
  • progesterone Eli Lilly, Indianapolis, IN
  • PE-50 polyethylene tubing
  • Lamprey l-LHRH-III caused FSH release in a dose-related fashion, with a minimal effective concentration (MEC) of 10 "9 M (the lowest concentration tested) or lower, and a maximal effect at about 10 "6 M. Thereafter, release of FSH levelled off through the highest concentration tested (10" M).
  • MEC minimal effective concentration
  • Lamprey l-LHRH-I caused a small but statistically significant release of FSH at a concentration of 10 s M; the amount of FSH released was significantly less than that caused by l-LHRH-III at the two concentrations tested (10 ⁇ 6 and 10 "5 M).
  • m-LHRH produced equivalent levels of FSH release at the two concentrations tested (4 x 10 "9 and 2 x 10 "8 M) as compared to the levels induced by l-LHRH-III. See Table 2.
  • Table 2 Table 2
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; *** signifies p ⁇ 0.001; and **** signifies p ⁇ 0.0001 versus KRB control
  • l-LHRH-III had a much weaker effect on LH release. In fact, l-LHRH-III only caused the release of significant and comparable concentrations of LH at the three highest concentrations tested (10 6 - 10 "4 M). We found that l-LHRH-I was inactive at the two concentrations tested (10 ⁇ 6 and 10 '5 M). Mammalian LHRH gave a dose-related stimulatory effect on LH release, and was active at the lowest concentration tested (4 x 10 "9 M). See Table 3.
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; versus KRB control
  • Salmon (s)-LHRH stimulated the release of both FSH and LH at the two concentrations tested (10 " ⁇ and 10"" M). See Tables 4 and 5.
  • Chicken (c) LHRH-II stimulated LH release at doses from 10' 8 to 10" M, but the dose effect was not statistically significant.
  • the c-LHRH-II had equivalent LH-releasing activity to that of m-LHRH, but l-LHRH-III showed no LH-releasing activity in this experiment.
  • the c-LHRH-II only significantly increased FSH release at the highest concentration tested (10 "6 M).
  • the MEC for l-LHRH-III for a statistically significant release of FSH was two orders of magnitude lower than that for c-LHRH-II.
  • n 6 in each case; * signifies p ⁇ 0.05; ** signifies p ⁇ 0.01; and *** signifies p ⁇ 0.001 versus KRB control
  • n 6 in each case; * signifies p ⁇ 0.05 versus KRB control
  • l-LHRH-III is the first highly specific and potent FSH-releasing peptide discovered.
  • the l-LHRH-III behaves completely differently from the other polypeptides tested.
  • Salmon LHRH and chicken LHRH-II had low potency, and lacked specificity for FSH release.
  • the in vivo assays using the other known vertebrate LHRH's showed that only one of them, c-LHRH-II, possessed even slight selectivity for FSH release.
  • l-LHRH-III is a highly conserved peptide in vertebrates, and in particular that it or a closely related peptide is the mammalian peptide hormone responsible for the potent and specific release of FSH. If l-LHRH-III is not identical to the mammalian FSH-RF, the degree of homology between the two is quite high.
  • Mammalian m-LHRH and l-LHRH-III were approximately equipotent toward releasing FSH.
  • the decreased potency of l-LHRH-III toward releasing LH is probably accounted for by the fact that l-LHRH-III only has 60% homology with m-LHRH (see Table 1).
  • the differences in sequences are accounted for by the differing amino acids in positions 5-8, which presumably cause a drastic decrease in LH-releasing activity and an increase in FSH-releasing capabilities. It is probable that the tetrapeptide l-LHRH-III 5-8 binds to the active site of a putative specific FSH-RF receptor.
  • FSH-RF receptor confers this specificity for FSH release, whereas the LHRH receptors stimulate the release of both hormones, albeit with a greater sensitivity for LH than FSH release.
  • FSH-RF receptors may reside on gonadotropes that contain only FSH.
  • LHRH receptors may cause release of both hormones from gonadotropes that contain both FSH and LH.
  • LHRH receptors may also be located on gonadotropes that only contain LH.
  • Pulsatile gonadotropin release in the rat is characterized by simultaneous pulses of FSH and LH, by pulses of LH alone, and by pulses of FSH alone. We hypothesize that the first two types of pulses may be accounted for by LHRH, and the third by FSH-RF.
  • FSH-RF farnesoid follicles and subsequent ovulations
  • FSH-RF may be used as a drug to increase fertility in humans.
  • peptides are expected to be agonists or "superagonists" of l-LHRH-III. These agonists will be prepared and tested in similar assays. Particular examples include peptides in which (a) the Asp 6 amino acid residue has been replaced with another amino acid residue (naturally occurring or xenobiotic); or (b) in which the Pro 9 residue has been replaced with ProNHEt (prolyl ethyl amide) and the Gly 10 -NH 2 has been deleted; or (c) both. Examples of such agonists include the following: pGlu-His-T ⁇ -Ser-His-Asp-T ⁇ -Lys-(ProNHEt) (SEQ. ID NO. 6)
  • inhibitory analogs of the peptide, or antibodies against the peptide may be used as potent antifertility drugs.
  • Monoclonal or polyclonal antibodies against the peptide may be raised using standard techniques, initially conjugating the peptide to a carrier such as bovine serum albumin or keyhole limpet hemocyanin.
  • a carrier such as bovine serum albumin or keyhole limpet hemocyanin.
  • antagonists include peptides in which one or more of residues 1, 2, 3, 6, and 10 have been replaced with another amino acid residue (naturally occurring or xenobiotic). Examples of such antagonists include the following:
  • the effect of the peptide, its agonists, and its antagonists will be characterized in rats, and then in large mammals, such as sheep and pigs. After successful testing in large mammals, in vivo tests in primates will be conducted, in monkeys and in humans, in accordance with applicable laws and regulations.
  • the peptide, an agonist, or an antagonist, combined with a pharmaceutically acceptable carrier may be administered to mammals, including humans, intravenously, subcutaneously, percutaneously, intramuscularly, or intranasally to increase fertility. It may also be administered to other vertebrates to increase fertility, for example sheep, cattle, pigs, chickens, turkeys, channel catfish, tilapia, and koi.
  • the active compound may be administered as a pharmaceutically acceptable salt, such as an acid addition salt; metal complex, e.g. with zinc, iron; or the like (which are considered salts for pu ⁇ oses herein).
  • a pharmaceutically acceptable salt such as an acid addition salt; metal complex, e.g. with zinc, iron; or the like (which are considered salts for pu ⁇ oses herein).
  • acid addition salts are hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate, and the like.
  • Intravenous or other injections may be administered in isotonic saline, phosphate buffers, and the like. The dosage will vary depending on the specific pu ⁇ ose for which the peptide is administered; appropriate dosages may readily be determined by those of skill in the art, an
  • a patient experiencing infertility of unknown cause may be tested for 1- LHRH-III or FSH deficit through means otherwise known in the art, such as radio immunoassay.
  • Abnormally low FSH levels may indicate a deficiency in l-LHRH-III.
  • Such patients may be tested for a positive response to exogenous l-LHRH-III. If administration of exogenous l-LHRH-III produces an increase in FSH, that finding indicates that administration of exogenous l-LHRH-III is a potential treatment for infertility.
  • the l-LHRH-III may be synthesized through any of various means known in the art, for example, synthesis on a solid-state peptide synthesizer, or expression of a cloned gene in E. coli.
  • Xaa at 2 is (D-p-Cl-Phe)
  • Xaa at 3 is (D-Trp)
  • Xaa at 6 is (D-L-Arg-Et2)
  • Xaa at 10 is (D-Ala-NH2)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Reproductive Health (AREA)
  • Wood Science & Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Insects & Arthropods (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)

Abstract

La LH-RH-III de la lamproie est un puissant facteur libérateur de F.S.H., et il peut être utilisé pour stimuler la fécondité. Des antagonistes de la LH-RH-III de la lamproie peuvent être utilisés pour inhiber la fécondité.
EP98926280A 1997-06-04 1998-06-03 Peptides liberateurs de f.s.h. Withdrawn EP0996457A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US86915397A 1997-06-04 1997-06-04
US869153 1997-06-04
PCT/US1998/011512 WO1998055136A1 (fr) 1997-06-04 1998-06-03 Peptides liberateurs de f.s.h.

Publications (2)

Publication Number Publication Date
EP0996457A1 true EP0996457A1 (fr) 2000-05-03
EP0996457A4 EP0996457A4 (fr) 2001-09-19

Family

ID=25353027

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98926280A Withdrawn EP0996457A4 (fr) 1997-06-04 1998-06-03 Peptides liberateurs de f.s.h.

Country Status (4)

Country Link
EP (1) EP0996457A4 (fr)
JP (1) JP2000513749A (fr)
CA (1) CA2293664A1 (fr)
WO (1) WO1998055136A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6635740B1 (en) 1997-03-27 2003-10-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Ligand/lytic peptide compositions and methods of use
HU221407B1 (hu) 1997-03-28 2002-09-28 Gyula Magvasi Ektodermális eredetû szövetekben fellépõ tumoros burjánzást gátló hatóanyag és készítmény, valamint eljárás elõállításukra
DE10050831A1 (de) * 2000-10-05 2002-05-02 Veyx Pharma Gmbh Verfahren zum Zyklusstart bei weiblichen Zuchttieren
CN101264096B (zh) * 2007-03-12 2011-11-09 中国医学科学院药物研究所 人参皂苷Rg1在制备生精产品中的应用
JP5764854B2 (ja) * 2009-11-05 2015-08-19 株式会社サウスプロダクト ポリクローナル抗体およびその利用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004927A1 (fr) * 1994-08-10 1996-02-22 Sandor Lovas NOUVEAUX ANALOGUES DE GnRH A EFFETS ANTITUMORAUX ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721775A (en) * 1985-08-26 1988-01-26 Board Of Regents, The University Of Texas System Effective peptides related to the luteinizing hormone releasing hormone from L-amino acids
US4973577A (en) * 1986-04-04 1990-11-27 The Salk Institute For Biological Studies FSH-releasing peptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004927A1 (fr) * 1994-08-10 1996-02-22 Sandor Lovas NOUVEAUX ANALOGUES DE GnRH A EFFETS ANTITUMORAUX ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1990 YU W H ET AL: "SELECTIVE FSH-RELEASING ACTIVITY OF 9-D TRYPTOPHAN GAP-1-13 COMPARISON WITH GONADOTROPIN-RELEASING ABILITIES OF ANALOGS OF GAP AND NATURAL LHRHS" Database accession no. PREV199191064460 XP002170295 & BRAIN RESEARCH BULLETIN, vol. 25, no. 6, 1990, pages 867-874, ISSN: 0361-9230 *
MEZOE I ET AL: "SYNTHESIS OF GONADOTROPIN-RELEASING HORMONE III ANALOGS. STRUCTURE - ANTITUMOR ACTIVITY RELATIONSHIPS" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 40, October 1997 (1997-10), pages 3353-3358, XP000749516 ISSN: 0022-2623 *
See also references of WO9855136A1 *
SOWER S A ET AL: "PRIMARY STRUCTURE AND BIOLOGICAL ACTIVITY OF A THIRD GONADOTROPIN- RELEASING HORMONE FROM LAMPREY BRAIN" ENDOCRINOLOGY,US,BALTIMORE, MD, vol. 132, no. 3, 1993, pages 1125-1131, XP002067663 ISSN: 0013-7227 *
YU WEN H ET AL: "A hypothalamic follicle-stimulating hormone-releasing decapeptide in the rat." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 94, no. 17, August 1997 (1997-08), pages 9499-9503, XP002170294 1997 ISSN: 0027-8424 *

Also Published As

Publication number Publication date
JP2000513749A (ja) 2000-10-17
EP0996457A4 (fr) 2001-09-19
WO1998055136A1 (fr) 1998-12-10
CA2293664A1 (fr) 1998-12-10

Similar Documents

Publication Publication Date Title
US5084555A (en) An octapeptide bombesin analog
JP4346115B2 (ja) Ｌｈ−ｒｈペプチド類似体、その使用及びそれを含有する薬用組成物
US7566777B2 (en) Genes encoding hormone and lytic peptides
US6307017B1 (en) Octapeptide bombesin analogs
Vilchez-Martinez et al. Paradoxical effects of D-Trp6-luteinizing hormone-releasing hormone on the hypothalamic-pituitary-gonadal axis in immature female rats
EP0592512A1 (fr) Analogues non desensibilisants de gonadoliberine et d'autres ligands biologiquement actifs
AU662496B2 (en) LHRH-antagonists
EP0996457A1 (fr) Peptides liberateurs de f.s.h.
Haviv et al. Active reduced-size hexapeptide analogs of luteinizing hormone-releasing hormone
US6300471B1 (en) FSH-releasing peptides
EP0988048A1 (fr) Compositions de peptides lytiques/ligands et leurs procedes d'utilisation
US6407205B1 (en) FSH-releasing peptides
Schally et al. Stimulatory and inhibitory analogs of luteinizing hormone releasing hormone (LHRH)
US5382568A (en) Decapeptide having dopamine stimulating activity
Coy et al. Suppression of gonadotropin release and ovulation in animals by inhibitory analogs of luteinizing hormone-releasing hormone
Schally et al. Hypothalamic hormones regulating pituitary (and other) functions: their physiology and biochemistry as well as recent studies with their synthetic analogues
SCHALLY Aspects of hypothalamic regulation of the pituitary gland with major emphasis on its implications for the control of reproductive processes
Schally et al. Physiological, veterinary and clinical effects of hypothalamic releasing hormones (RH), especially LH-RH
Chihara et al. AV Schally*, DH Coy*, A. Arimura*, TW Redding*, AJ Kastin*, C. Meyers*, J. Seprodi*, R. Chang*, W.-Y. Huang
Bouchard et al. Comparison of the mechanisms of action of LHRH analogs and steroids in the treatment of endometriosis
Sherwood et al. Primary Structure and Function of Three Gonadotropin
SCHALLY et al. HORMONES (RI-I), ESPECIALLY LH-RH
CHAO OPIOID MODULATION OF THE RELEASE OF LUTEINIZING HORMONE (PITUITARY, CELL CULTURE, DYNORPHIN, MET-ENKEPHALIN)
McCANN et al. Hypothalamic Releasing Factors and
NEKOLA et al. RECENT ADVANCES IN THE DEVELOPMENT OF LHRH ANTAGONISTS

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19991223

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 38/08 A, 7C 07K 7/23 B

A4 Supplementary search report drawn up and despatched

Effective date: 20010806

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20020422

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20031203