WO1982000004A1 - Traitement contraceptif des mammiferes males - Google Patents

Traitement contraceptif des mammiferes males Download PDF

Info

Publication number
WO1982000004A1
WO1982000004A1 PCT/US1980/000818 US8000818W WO8200004A1 WO 1982000004 A1 WO1982000004 A1 WO 1982000004A1 US 8000818 W US8000818 W US 8000818W WO 8200004 A1 WO8200004 A1 WO 8200004A1
Authority
WO
WIPO (PCT)
Prior art keywords
pro
phe
group
trp
peptide
Prior art date
Application number
PCT/US1980/000818
Other languages
English (en)
Inventor
Inst Biological Studies Salk
W Vale
C Rivier
J Rivier
Original Assignee
Salk Inst For Biological Studi
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 Salk Inst For Biological Studi filed Critical Salk Inst For Biological Studi
Priority to PCT/US1980/000818 priority Critical patent/WO1982000004A1/fr
Priority to AU70383/81A priority patent/AU538564B2/en
Priority to GB8201856A priority patent/GB2089209B/en
Priority to US06/272,968 priority patent/US4377574A/en
Priority to ZA814141A priority patent/ZA814141B/xx
Priority to NZ197464A priority patent/NZ197464A/xx
Priority to PH25808A priority patent/PH16650A/en
Priority to BE0/205217A priority patent/BE889388A/fr
Publication of WO1982000004A1 publication Critical patent/WO1982000004A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptides which inhibit the release of gonadotropins by the pituitary gland in mammalians, including humans and more specifically to methods of preventing conception by administering to male mammals such peptides which inhibit gonadal function and the release of the steroidal hormones, progesterone and testosterone.
  • the pituitary gland is attached by a stalk to the region in the base of the brain known as the hypothalamus.
  • the pituitary gland has two lobes, the anterior and the posterior lobes.
  • the posterior lobe of the pituitary gland stores and passes onto the general circulation two hormones manufactured in the hypothalamus, these being vasopressin and oxytocin.
  • the anterior lobe of the pituitary gland secretes a number of hormones, which are complex protein or glyco-protein molecules that travel through the bloodstream to various organs and which, in turn, stimulate the secretion into the bloodstream of other hormones from the peripheral organs..
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • LRF hypothalamic hormone which acts as a releasing factor for LH
  • LRF has been isolated and characterized as a decapeptide having the following structure: p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2
  • Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked to the amino group of the other acid.
  • the formula for LRF, as represented above, is in accordance with conventional representation of peptides where the amino group appears to the left and the carboxyl group to the right. The position of the amino acid residue is identified by numbering the amino acid residues from left to right. In the case of LRF, the hydroxyl portion of the carboxyl group of glycine has been replaced with an amino group (NH 2 ) .
  • the abbreviations for the individual amino acid residues above are conventional and are based on the trivial name of the amino acid: where p-Glu is pyroglutamic acid.
  • amino acids of the peptides of the invention are of the L-configuration unless noted otherwise. It is known that the substitution of D-amino acids for Gly in the 6-position of the LRF decapeptide can provide a peptide material having from about 1 to 35 times greater potency, relative to LRF, to effect the release of LH and other gonadotropins by the pituitary gland of mammalians. The releasing effect is obtained when the LRF analog, referred to as an LRF agonist, is introduced into the bloodstream of a mammalian.
  • LRF antagonists having an inhibitory effect on the release of LH and other gonadotropins by the pituitary gland of mammalians.
  • varying degrees of inhibition of the release of LH are obtained when His is deleted (des His) or replaced by D-Ala, D-Phe or Gly.
  • the inhibitory effect of such peptides modified at the 2-position can be further enhanced when a D-amino acid is substituted for Gly in the 6-position of the decapeptides.
  • the peptide: [des His 2 , D-Ala 6 ] LRF i.e., pGlu-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH 2
  • LRF is 3 times more potent as an inhibitor for the release of gonadotropins than is the same peptide where Gly is present in the 6-position rather than D-Ala.
  • Some female mammalians who have no ovulatory cycle and who show no pituitary or ovarian defect begin to secrete normal amounts of the gonadotropins LH and FSH after the appropriate administration of LRF.
  • LRF is considered suitable for the treatment of those cases of infertility where a functional defect resides in the hypothalamus.
  • LRF antagonists have been used to prevent ovulation.
  • potent agonists have exhibited potential use as a contraceptive by substantially decreasing the sperm count in male mammals; however, more effective methods of contraception for male mammals using LRF analogs were sought.
  • the present invention provides a method for contraceptive treatment of male mammals, including humans, using peptides which strongly inhibit the release of gonadotropins.
  • the administration of these LRF analogs that are strongly antagonistic to LRF has an inhibitory effect on the reproduction processes of male mammals and accomplishes such a substantial decrease in the sperm count that fertilization is effectively prevented.
  • LRF antagonists which strongly inhibit the secretion of gonadotropins by the pituitary gland of mammalians, including humans, and inhibit the release of steroids by the gonads can be employed as male contraceptives because they are effective at low enough dosage levels, i.e. not more than about 3 milligrams per day per kilogram of body weight, to eliminate undersirable dermatological and other side effects.
  • the peptide has a binding affinity at least about 15 times that exhibited by LRF.
  • the peptide should have an ICR 50 of less than 1/1, and can be administered by any suitable and convenient method, such as orally, by injection or subcutaneously. Oral administration is preferred for humans; however, injection may be preferably for veterinary uses.
  • the peptide can be combined with suitable pharmaceutically acceptable carriers or dilluents, such as vegetable oil, sugars, corn starch, polysaccharides and gums.
  • suitable pharmaceutically acceptable carriers or dilluents such as vegetable oil, sugars, corn starch, polysaccharides and gums.
  • the peptide might be administered daily for 7 consecutive days out of each month. Alternatively, it might be administered each day at a somewhat lower level together with suitable androgens.
  • Such peptides are often administered in the form of pharmaceutically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g., with zinc, iron or the like (which are considered as addition salts for purposes of this application) .
  • acid addition salts are hydrochloride. hydrobromide, sulphate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like.
  • LRF antagonists wherein there are substitutions in the 1- and 6-positions, wherein substituted D-Phe is present in the 2-position and wherein D-Trp is present in the 3-position.
  • the 1-position may contain dehydro-Pro, dehydro-D-Pro, Thz or D-Thz.
  • the 6-position may contain either D-Trp of (imBzl)D-His.
  • certain substitutions may optionally be made in the 7 and 10 positions.
  • dehydro Pro is meant 3,4 dehydroProline, C 5 -H 6 O 2 N, and when R 1 is an acyl radical, it is attached to the nitrogen.
  • Thz meta-thiazolidine-2-carboxylic acid, C 4 H 7 O 2 NS, which can be prepared by the treatment of cysteine hydrochloride with formaldehyde.
  • R 1 is an acyl radical, it is attached to the nitrogen; for example Ac-Thz is prepared by the reaction of Thz with acetic anhydride.
  • the peptides of the present invention are represented by the following formula: R 1 -R 2 -R 3 -D-Trp-Ser-Tyr-R 4 -Leu-Arg-Pro-Gly-NH 2
  • R 1 is selected from the group consisting of hydrogen, formyl, acetyl, acrylyl, benzoyl and allyl
  • R 2 is selected from the group consisting of dehydro Pro, dehydro D-Pro, Thz and D-Thz
  • R is selected from the group consisting of pCl-D-Phe, pF-D-Phe, pNO 2 -D-Phe and 3,4 C1-D-Phe
  • R 4 is selected from the group consisting of D-Trp and (imBzl)D-His.
  • Leu may be substituted by N ⁇ MeLeu
  • Gly-NH 2 may be substituted by NHCH 2 CH 3 or some other alkyl amide having 1 to 5 carbon atoms.
  • Other equivalent acyl groups can be used at R 1 .
  • the peptides of the present invention can be synthesized by a solid phase technique using a chloromethylated resin for those peptides wherein an alkyl amide is present and a benzhydrylamine (BHA) resin for those peptides wherein Gly-NH 2 is present. The synthesis is conducted in a manner to stepwise add the amino acids in the chain in the manner set forth in detail in the U.S. Patent No. 4,072,668, the disclosure of which is incorporated herein by reference. Side-chain protecting groups, as are well known in the art, are added to Ser, Tyr, Arg and His before these amino acids are coupled to the chain being built up upon the resin.
  • Such a method provides the fully protected intermediate peptidoresin.
  • the fully protected peptide can be cleaved from the resin support by aminolysis, as is well known in the art, to yield the fully protected amide intermediate.
  • the intermediates of the invention may be represented as: X 1 -R 2 -R 3 -D-Trp-Ser (X 2 ) -Tyr (X 3 ) -R 4 -Leu- Arg(X 4 )-Pro-X 5 wherein: X is an ⁇ -amino protecting group of the type known to be useful in the art in the stepwise synthesis of polypeptides and when R, in the desired peptide composition is a particular acyl group, that group may be used as the protecting group.
  • acyl-type protecting groups such as formyl, trifluoroacetyl, phthalyl, Tos, benzoyl, benzensulfonyl, nitrophenylsulfenyl, tritylsulfenyl, o-nitrophenoxyacetyl, acrylyl, chloroacetyl, acetyl and ⁇ -chlorobutyryl;
  • aromatic urethan-type protecting groups e.g., benzyloxycarbonyl and substituted benzyloxycarbonyl, such as p-chloro-benzyloxyerarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyl-oxycarbonyl and p-methoxybenzyloxycarbonyl
  • aliphatic urethan protecting groups such as terbutyloxycarbonyl (Boc) , di
  • X 2 is a protecting group for the alcoholic hydroxyl group of Ser and is selected from the group consisting of acetyl, benzoyl, tetrahydropyranyl, tert-butyl, trityl, benzyl and 2,6-dichlorobenzyl.
  • X 3 is a protecting group for the phenolic hydroxyl group of Tyr selected from the group consisting of tetrahydropyranyl, tert-butyl, trityl, benzyl, benzyloxycarbonyl, 4-bromobenzyloxycarbonyl and
  • X 4 is a protecting group for the guanidmo group of Arg and is selected from the group consisting of nitro, Tos, benzyloxycarbonyl, adamantyloxycarbonyl, and Boc; alternatively X 4 may be hydrogen, which means there are no protecting groups on the side chain nitrogen atoms of arginine.
  • X 5 is selected from dimethylamine, alkylamine of 1 to 5 carbon atoms, phenethylamine, O-CH 2 - [resin support] or Gly-O-CH 2 - [resin support] or Gly-NH- [resin support] .
  • the criterion for selecting side chain protecting groups for X 2 -X 4 are that the protect ing group must be stable to the reagent under the reaction conditions selected for removing the ⁇ r-amino protecting group at each step of the synthesis, the protecting group must not be split off under coupling conditions and the protecting group must be removable upon completion of the synthesis of the desired amino acid sequence under reaction conditions that will not alter the peptide chain.
  • the ester moiety of one of the many functional groups of the polystyrene resin support is being represented.
  • the X 5 group is Gly-NH-[resin support]
  • an amide bond connects Gly to BHA resin or to a paramethyl BHA resin.
  • R 1 is acetyl, formyl, acrylyl, benzoyl, or allyl, it may be employed as the X 1 protecting group for the ⁇ —amino group of proline or Thz, in which case it can be added to proline or to Thz before it is coupled to the peptide chain.
  • Acetyl is abbreviated as Ac, and acrylyl is abbreviated as Acr.
  • a reaction may be carried out with the peptide on the resin, e.g. reacting with acetic acid in the presence of dicyclohexyl carbodiimide (DCC) or with acetic anhydride,
  • DCC dicyclohexyl carbodiimide
  • acetic anhydride acetic anhydride
  • Deprotection of the peptides as well as cleavage of the peptide from the benzhydrylamine resin takes place at 0oC with hydrofluoric acid (HF) .
  • Anisole is added to the peptide prior to treatment with HF. After the removal of HF, under vacuum, the cleaved, deprotected peptide is treated with ether, decanted, taken in dilute acetic acid and lyophilized.
  • peptides of the invention are considered to be effective at levels of 200 micrograms per kilogram of body weight. It is presently preferred to use dosage levels in the range of from about 0.1 to about 3 milligrams per kilogram of body weight when these antagonists are administered as contraceptives to male mammals on a regular basis; however, it is not certain that body weight is true criterion so lesser amounts may be effective.
  • dosage levels in the range of from about 0.1 to about 3 milligrams per kilogram of body weight when these antagonists are administered as contraceptives to male mammals on a regular basis; however, it is not certain that body weight is true criterion so lesser amounts may be effective.
  • a BHA resin is used, and Boc-protected Gly is coupled to the resin over a 2-hour period in CH 2 Cl 2 using a 3-fold excess of Boc derivative and DCC as an activating reagent.
  • the glycine residue attaches to the BHA residue by an amide bond.
  • step 13 an aliquot is taken for a ninhydrin test: if the test is negative, go back to step 1 for coupling of the next amino acid; if the test is positive or slightly positive, go back and repeat steps 9 through 13.
  • N ⁇ Boc protection is used for each of the remaining amino acids throughout the synthesis.
  • the side chain of Arg is protected with Tos.
  • Bzl is used as a side chain protecting group for the hydroxyl group of Ser, and 2-6 dichlorobenzyl is used as the side chain protecting group for the hydroxyl group of Tyr.
  • Boc-Arg(Tos) and Boc-D-Trp which have low solubility in CH 2 Cl 2 , are coupled using DMF.
  • the peptide is assayed in vitro using dissociated rat pituitary cells maintained in culture for 4 days prior to the assay.
  • the levels of LH mediated in response to the application of peptides is assayed by specific radioimmunoassay for rat LH.
  • Control dishes of cells receive LRF only (3 nanomolar) .
  • Experimental dishes receive a measure 3 nanomolar in LRF plus a measure having a concentration of test peptide ranging from 1 to 100 nanomolar.
  • the amount of LH secreted in the samples treated only with LRF is compared with that secreted by the samples treated with the peptide plus LRF to determine the ratio at which an amount of the antagonist will inhibit the activity of a certain amount of LRF.
  • Results are calculated and expressed as the molar concentration ratio of test peptide to LRF (antagonist/LRF) required to reduce the amount of LH released by 3 nanomolar LRF to 50 percent of the control value (ICR 50 ) .
  • the peptide to be considered effective for use in the method of the present invention it should have an ICR 50 of less than 1/1.
  • the Example I peptide has an ICR 50 of 0.043/1 and a binding affinity about 25 times that of LRF.
  • the peptide is used at a level effective to reduce testes and seminal vesicles weights and also to inhibit spermatogenesis after a 14-day administration to male rats.
  • Testosterone (T) levels of antagonist-treated male rats are comparable to those of control animals within one week following cessation of treatment for 14 days. Prostate weights of male rats recover in 2-3 weeks and seminal vesicles weights in 4-5 weeks. It is preferred to use dosage levels in the range of from about 0.1 to about 1 milligram per rat per day, which can be administered without detrimental side effects. It may be possible to use lower levels of antagonists to achieve similar results.
  • EXAMPLE II EXAMPLE II
  • Male rats (about 320 grams each) are each treated with 1 milligram of the peptide synthesized in Example I, once a day, for 14 days by injection in 0.2 ml. of corn oil. All the rats show a decrease in tester and seminal vesicles weight, spermatogenesis and plasma androgen levels. Moreover, immunoreactive gonadotropin levels, i.e. LH, FSH, Testosterone and dihydrotestorone (DHT) in the treated male animals were decreased relative to control animals. Histological examination of the testes following the 14-day treatment reveals arrested spermatogenesis for a period up to several weeks following cessation of the daily injections. The rats are incapable of causing fertilization after treatment for about 7 consecutive days.
  • immunoreactive gonadotropin levels i.e. LH, FSH, Testosterone and dihydrotestorone (DHT)
  • testes and seminal vesicle weights and spermatogenesis ultimately occurs following cessation of the 14-day peptide administration. After about four weeks, the testes weights are equal to about 80% that of the control group, and about seven days thereafter good spermatogenesis is apparent in a majority of the tubules.
  • the peptide tested is useful for contraceptive treatment to prevent reproduction by male mammals without harmful side effects or irreversible damage.
  • R 1 -R 2 -R 3 -D-Trp-Ser-Tyr-R 4 -Leu-Arg-Pro-Gly-NH 2 are synthesized as set forth below:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth 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

Des peptides, qui sont des analogues LRF qui inhibent la secretion des gonadotropines par la glande pituitaire et inhibent la liberation de steroides par les gonades, peuvent etre des contraceptifs efficaces lorsqu'ils sont administres a des mammiferes males. Les peptides sont des antagonistes de LRF ayant une affinite de liaison au moins quinze fois environ superieure a celles du LRF et ont un ICR50 inferieur a 1/1. Des exemples de peptides qui peuvent etre utilises sont ceux qui possedent la structure suivante: R1-R2-R3-D-Trp-Ser-Tyr-R4-Leu-Arg-Pro-Gly-NH2 ou R1 est selectionne parmi le groupe constitue de l'hydrogene, le formyle, l'acetyle, l'acrylile, le benzoyle, et l'allyle; R2 est selectionne parmi le groupe constitue de dehydro Pro, dehydro D-Pro, Thz et D-Thz; R3 est selectionne parmi le groupe constitue de pCl-D-Phe, pF-D-Phe, pXNO2-OD-Phe et Cl-D-Phe 3, 4; R4 est selectionne parmi le groupe constitue de D-Trp et (imBzl) D-His; et Leu peut etre substitue par N(Alpha)Ne- Leu.
PCT/US1980/000818 1980-06-26 1980-06-26 Traitement contraceptif des mammiferes males WO1982000004A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PCT/US1980/000818 WO1982000004A1 (fr) 1980-06-26 1980-06-26 Traitement contraceptif des mammiferes males
AU70383/81A AU538564B2 (en) 1980-06-26 1980-06-26 Contraceptive treatment of male mammals
GB8201856A GB2089209B (en) 1980-06-26 1980-06-26 Contraceptive treatment of male mammals
US06/272,968 US4377574A (en) 1980-06-26 1981-06-12 Contraceptive treatment of male mammals
ZA814141A ZA814141B (en) 1980-06-26 1981-06-18 Contraceptive treatment of male mammals
NZ197464A NZ197464A (en) 1980-06-26 1981-06-18 Inhibiting spermatogenesis in mammals using a peptide type l.r.f.antagonist
PH25808A PH16650A (en) 1980-06-26 1981-06-23 Contraceptive treatment of male mammals
BE0/205217A BE889388A (fr) 1980-06-26 1981-06-25 Procede inhibant la liberation des gonadotropines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1980/000818 WO1982000004A1 (fr) 1980-06-26 1980-06-26 Traitement contraceptif des mammiferes males
WOUS80/00818800626 1980-06-26

Publications (1)

Publication Number Publication Date
WO1982000004A1 true WO1982000004A1 (fr) 1982-01-07

Family

ID=22154416

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1980/000818 WO1982000004A1 (fr) 1980-06-26 1980-06-26 Traitement contraceptif des mammiferes males

Country Status (6)

Country Link
BE (1) BE889388A (fr)
GB (1) GB2089209B (fr)
NZ (1) NZ197464A (fr)
PH (1) PH16650A (fr)
WO (1) WO1982000004A1 (fr)
ZA (1) ZA814141B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0122712A2 (fr) * 1983-03-10 1984-10-24 The Salk Institute For Biological Studies GnRH antagonistes

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3835108A (en) * 1972-02-15 1974-09-10 American Home Prod Process for preparing the releasing hormone of luteinizing hormone(lh)and of follicle stimulating hormone(fsh),salts and compositions thereof,and intermediates therefor
US3880825A (en) * 1972-09-26 1975-04-29 Daiichi Seiyaku Co Des-His{hu 2{b ,Ala{hu 2 {b and Phe{hu 3,5 {b analogs of luteinizing hormone
US4002738A (en) * 1975-05-30 1977-01-11 Abbott Laboratories Treatment of specified neoplasias
US4005194A (en) * 1975-06-23 1977-01-25 Abbott Laboratories Treatment of prostatic hyperplasia
US4071622A (en) * 1976-02-11 1978-01-31 Abbott Laboratories Treatment of a mammary or DMBA inducible tumor
US4218439A (en) * 1977-07-14 1980-08-19 The Salk Institute For Biological Studies Peptide which inhibits gonadal function
US4234571A (en) * 1979-06-11 1980-11-18 Syntex (U.S.A.) Inc. Nonapeptide and decapeptide derivatives of luteinizing hormone releasing hormone
US4244946A (en) * 1979-06-11 1981-01-13 The Salk Institute For Biological Studies Water-soluble peptides affecting gonadal function

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3835108A (en) * 1972-02-15 1974-09-10 American Home Prod Process for preparing the releasing hormone of luteinizing hormone(lh)and of follicle stimulating hormone(fsh),salts and compositions thereof,and intermediates therefor
US3880825A (en) * 1972-09-26 1975-04-29 Daiichi Seiyaku Co Des-His{hu 2{b ,Ala{hu 2 {b and Phe{hu 3,5 {b analogs of luteinizing hormone
US4002738A (en) * 1975-05-30 1977-01-11 Abbott Laboratories Treatment of specified neoplasias
US4005194A (en) * 1975-06-23 1977-01-25 Abbott Laboratories Treatment of prostatic hyperplasia
US4071622A (en) * 1976-02-11 1978-01-31 Abbott Laboratories Treatment of a mammary or DMBA inducible tumor
US4218439A (en) * 1977-07-14 1980-08-19 The Salk Institute For Biological Studies Peptide which inhibits gonadal function
US4234571A (en) * 1979-06-11 1980-11-18 Syntex (U.S.A.) Inc. Nonapeptide and decapeptide derivatives of luteinizing hormone releasing hormone
US4244946A (en) * 1979-06-11 1981-01-13 The Salk Institute For Biological Studies Water-soluble peptides affecting gonadal function

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Acta Endocr. 84, Suppl. 208, Published 1977, J. Sandow, et al: Page 33 *
Am. J. Obstetrics And Gynecology, Vol. 114, pages 423-442, published 1972, Schally, et al: *
Biochem. And Biophys. Res. Comm. Vol. 76, pages 855-862, Published 1977, Auclair, et al: *
Endocrinology, Vol. 101, pages 1890-1893, Published 1977, Auclair, et al: *
Endocrinology, Vol. 103, pages 641-643, Published 1977, Pelletier, et al: *
Fertility And Sterility, Vol. 27, pages 545-548, published 1976, Turner, et al: *
Int. J. Fertil., Vol. 22, page 77, Published 1977, Jaramillo, et al: *
J. Endocr., Vol. 48, pages 289-290, published 1970, Geller, et al: *
J. Endocr., Vol. 63, pages 399-406, published 1974, Fraser, et al: *
Peptides, pages 427-451, published 1976, Rivier, et al: *
The Effect of Immunization of Mature Male Guinea Pig with Luteinizing Hormone, pages 233-239, published 1973, Mitawi, et al: *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0122712A2 (fr) * 1983-03-10 1984-10-24 The Salk Institute For Biological Studies GnRH antagonistes
EP0122712A3 (fr) * 1983-03-10 1986-05-14 The Salk Institute For Biological Studies GnRH antagonistes

Also Published As

Publication number Publication date
ZA814141B (en) 1982-07-28
GB2089209B (en) 1984-09-05
NZ197464A (en) 1985-09-13
PH16650A (en) 1983-12-06
GB2089209A (en) 1982-06-23
BE889388A (fr) 1981-10-16

Similar Documents

Publication Publication Date Title
US4444759A (en) GnRH Antagonists II
US4565804A (en) GnRH Antagonists VI
US4547370A (en) GnRH Antagonists
US4569927A (en) GnRH Antagonists IV
EP0973801A1 (fr) ANTAGONISTES DE GnRH
US4661472A (en) GnRH antagonists IX
US4652550A (en) GnRH antagonists VII
EP0162575B1 (fr) Antagonistes GNRH VII
US4292313A (en) LRF Antagonists
US4409208A (en) GnRH antagonists
US4619914A (en) GNRH antagonists IIIB
US4740500A (en) GnRH antagonists VIII
US4382922A (en) Peptides affecting gonadal function
US4377574A (en) Contraceptive treatment of male mammals
EP0038135B1 (fr) Antagonistes du facteur "LRF"
US4307083A (en) LRF Antagonists
EP0122712A2 (fr) GnRH antagonistes
US4489061A (en) Treatment of male mammals
US4386074A (en) LRF Antagonists
WO1982000004A1 (fr) Traitement contraceptif des mammiferes males
IE58287B1 (en) Spiro-heteroazolones for treatment of diabetes complications
KR910002702B1 (ko) 펩티드의 제법
CA1186302A (fr) Antagonistes du lrf

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): AU GB

Kind code of ref document: A1

Designated state(s): AU GB