The Salk Institute for Biological Studies

Wayne D Kornreich

Jean E Rivier

Wylie W Vale, Jr

Jean-Francois Hernandez

Catherine L Rivier

John S Porter

Harry A Anderson

Jean F Hernandez

CRF antagonists

Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula (see SEQ ID NO:9): Y-Ser-Xaa.sub.2 -Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa.sub.12 -His-Leu-Leu-Arg-Glu-Val-Leu-Xaa.sub.20 -Xaa.sub.21 -Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-Xaa.sub.32 -Ser-Asn-Arg-Xaa.sub.36 -Leu-Xaa.sub.38 -Xaa.sub.39 -Ile-Xaa.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; Xaa.sub.2 is Glu or Gln; Xaa.sub.12 is Phe or D-Phe; Xaa.sub.20 is Ala or Glu; Xaa.sub.21 is Met or Nle; Xaa.sub.22 is Ala or Thr; Xaa.sub.23 is Arg or Lys; Xaa.sub.24 is D-Ala or Ala; Xaa.sub.25 is Glu or Asp; Xaa.sub.32 is D-His or His; Xaa.sub.36 is Lys or Arg; Xaa.sub.38 is Met, Nle or Leu; Xaa.sub.39 is Ala, Glu or Asp; Xaa.sub.41 is Ile or Ala; provided however that at least one of Xaa.sub.20 and Xaa.sub.39 is Ala and that the N-terminus may be shortened by a sequence of up to about 5 residues. By shortening the N-terminus by 11 residues, particularly potent CRF antagonists are created. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.

CRF analogs

Disclosed are improved CRF peptide antagonists such as those having the formula: Y-D-Phe-R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -Leu-R.sub.20 -Nle-R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -R.sub.26 -Leu-R.sub.28 -R.sub.29 -Gln-R.sub.31 -R.sub.32 -R.sub.33 -R.sub.34 -Arg-R.sub.36 -R.sub.37 -Nle-R.sub.39 -R.sub.40 -R.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; R.sub.13 is His, Tyr or Glu; R.sub.17 is Cys, Glu, Asn or Lys; R.sub.18 is Val, Nle or Met; R.sub.20 is D-Cys, Glu, D-Glu, Aib or D-Ala; R.sub.22 is Ala, Aib, Thr, Asp or Glu; R.sub.23 is Arg, Orn, Har or Lys; R.sub.24 is Ala or Aib; R.sub.25 is Asp or Glu; R.sub.26 is Gln, Asn or Lys; R.sub.28 is Ala or Aib; R.sub.29 is Gln, Aib or Glu, R.sub.31 is Ala or Aib; R.sub.32 is His, Aib, Gly, Tyr or Ala; R.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; R.sub.34 is Asn or Aib; R.sub.36 is Lys, Orn, Arg, Har or Leu; R.sub.37 is Leu or Try; R.sub.39 is Glu, Aib or Asp; R.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln. Specific CRF antagonists disclosed include [D-Phe.sup.12, D-Ala.sup.20, Nle.sup.21,38,]-rCRF(12-41), [D-Phe.sup.12, Nle.sup.21,38, Aib.sup.33 ]-rCRF(12-41) and (c 17-20) [D-Phe.sup.12, Cys.sup.17, D-Cys.sup.20, Nle.sup.21,38 ]-rCRF(12-41).

Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula: Y-R.sub.1 -R.sub.2 -R.sub.3 -R.sub.4 -R.sub.5 -Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-R.sub.20 -R.sub.21 -R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-R.sub.32 -Ser-Asn-Arg-Lys-Leu-R.sub.38 -R.sub.39 -Ile-R.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; R.sub.1 is Ser or desR.sub.1 ; R.sub.2 is Glu, Gln or desR.sub.2 ; R.sub.3 is Glu or desR.sub.3 ; R.sub.4 is Pro or desR.sub.4 ; R.sub.5 is Pro or desR.sub.5 ; R.sub.20 is Ala or Glu; R.sub.21 is Met or Nle; R.sub.22 is Ala or Thr; R.sub.23 is Arg or Lys; R.sub.24 is D-Ala or Ala; R.sub.25 is Glu or Asp; R.sub.32 is D-His or His; R.sub.38 is Met, Nle or Leu; R.sub.39 is Ala, Glu or Asp; R.sub.41 is Ile or Ala; provided however that at least one of R.sub.20 and R.sub.39 is Ala. One example is [Ala.sup.20 ]-oCRF. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.

Peptide N-alkylamides, and other C-terminal N-substituted amides, can be synthesized using solid-phase synthesis on a benzene-containing resin which is suitably methylated. Reactive amino groups are attached directly or indirectly to the methyl groups, for example, such as by reacting commercially available chloromethylated polystyrene resins with an alkylamine to create a resin-amine. The C-terminal amino acid of the desired peptide is linked to the resin-amine via an amide linkage, and the peptide is thereafter built in normal fashion. Treatment of the completed peptide intermediate with HF is effective to both effect deprotection and cleave the peptide from the resin in the form of the N-substituted amide. Examples include peptide N-ethylamides, N-fluoroethylamide, N-anilides and other substituted N-benzylamides.

Growing community of inventors

San Diego, CA, United States of America

Wayne D Kornreich