Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Corticotropin ; related peptides
Patent
1993-12-14
1996-04-23
Chan, Christina Y.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Corticotropin ; related peptides
530324, 530325, 930 21, 930 70, 930260, C07K 14695
Patent
active
055104584
DESCRIPTION:
BRIEF SUMMARY
This invention is directed to peptides and to methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to analogs of the hentetracontapeptide CRF, particularly antagonists thereof, to pharmaceutical compositions containing such CRF analogs and to methods of treatment of mammals using such CRF analogs.
BACKGROUND OF THE INVENTION
Experimental and clinical observations have supported the concept that the hypothalamus plays a key role in the regulation of adenohypophysial corticotropic cells secretory functions. Although over 25 years ago, it was demonstrated that factors present in the hypothalamus would increase the rate of ACTH secretion by the pituitary gland, when incubated in vitro or maintained in an organ culture, a physiologic corticotropin releasing factor (CRF) was not characterized until ovine CRF (oCRF) was characterized in 1981. As disclosed in U.S. Pat. No. 4,415,558, oCRF was found to have the formula (SEQ ID NO:1): Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His- Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln- Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala wherein the C-terminus is amidated. oCRF lowers blood pressure in mammals when injected peripherally and stimulates the secretion of ACTH and .beta.-endorphin.
Rat CRF(rCRF) was later isolated, purified and characterized as a hentetracontapeptide having the formula (SEQ ID NO:2): Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His- Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala- Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile, wherein the C-terminus is amidated, as described in U.S. Pat. No. 4,489,163. It is sometimes referred to as rat amunine. The formula of human CRF has now been determined to be the same as that of rCRF, and the terms rCRF and hCRF are used interchangeably. A CRF analog has been developed having a high alpha-helical forming potential and the formula (SEQ ID NO: 3): Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu- Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala- Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala, wherein the C-terminus is amidated; it is referred to as AHC (alpha-helical CRF) and is described in U.S. Pat. No. 4,594,329.
Synthetic rCRF, oCRF and AHC stimulate ACTH and .beta.-endorphin-like activities (.beta.-END-LI) in vitro and in vivo and substantially lower blood pressure when injected peripherally. Antagonists of these compounds are disclosed in U.S. Pat. No. 4,605,642, issued Aug. 12, 1986.
SUMMARY OF THE INVENTION
Analogs of these improved biological activity, e.g. CRF peptides have been discovered which exhibit longer lasting biological activity, and certain analogs which are of particular interest are novel CRF antagonists that have improved biological properties in comparison to known CRF antagonists. These peptides preferably have a specific D-isomer substitution in the 20-position or have Aib in certain selected positions, i.e. from position 20 to the C-terminus. The peptide antagonists preferably optionally also have D-Phe in the 12-position and norleucine in the 21 and 38 positions. Other optional substitutions may also be made throughout the molecule as previously taught. For example, a Leu residue in the 17-position and/or the 37-position substituted with a methyl group on its .alpha.-carbon atom is considered to enhance biopotency, and other Leu residues throughout the molecule, particularly in the 14- and 15-positions, may also be so substituted and employed in combination with the aforementioned substitutions. Beginning at the N-terminus, the peptide is shortened by the deletion of a sequence of 8 to about 11 residues to produce the antagonists, and it is preferably shortened by deletion of 11 residues. CRF agonists having similar substitutions also have increased biopotency and duration of bioactivity.
Pharmaceutical compositions in accordance with the invention include such CRF analogs, including the antagonists, or nontoxic addition salts thereof, dispersed in a pharmaceu
REFERENCES:
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patent: 5109111 (1992-04-01), Rivier et al.
patent: 5235036 (1993-10-01), Kornreich et al.
patent: 5245009 (1993-09-01), Kornreich et al.
patent: 5278146 (1994-01-01), Rivier et al.
Rivier et al., Science, vol. 224, pp. 889-891, (May 25, 1984).
Tache et al., "Role of CRF in Stress-Related Alterations of Gastric and Colonic Motor Function", Annals of the New York Academy of Sciences, vol. 697, pp. 233-243 (1993).
Hernandez et al., "Synthesis and Relative Potencies of New Constrained CRF Antagonists", J. Med. Chem. 1993, 36, pp. 2860-2867.
Hernandez Jean F.
Kornreich Wayne D.
Rivier Catherine L.
Rivier Jean E.
Vale, Jr. Wylie W.
Chan Christina Y.
The Salk Institute for Biological Studies
Wessendorf T. D.
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