CRF analogs

Details CRF analogs CRF analogs

1993-08-10

1995-08-08

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 2, 530324, 530325, C07K 14695, A61K 3835

Patent

active

054398851

ABSTRACT:
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.

REFERENCES:
patent: 3792033 (1974-02-01), Iselin et al.
patent: 5109111 (1992-04-01), Rivier et al.
patent: 5235036 (1993-08-01), Kornreich et al.
patent: 5245009 (1993-09-01), Kornreich et al.
patent: 5278146 (1994-01-01), Rivier et al.
Rivier et al., "Single Point D-Substituted Corticotropin-Releasing Factor Analogues: Effects on Potency and Physicochemical Characteristics", J. Med. Chem., vol. 36, No. 20, Oct. 1993, pp. 2851-2859.
Kornreich et al., "Alanine Series of Ovine Corticotropin Releasing Factor (oCRF): A Structure-Activity Relationship Study", Journal of Medicinal Chemistry, 1992, vol. 35, No. 10, pp. 1870-1876.

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