Constrained Corticotropin Releasing Factor Antagonists (Astressin Analogues) with Long Duration of Action in the Rat

• Published in: Journal of medicinal chemistry 1999-08, Vol.42 (16), p.3175-3182
• Main Authors: Rivier, Jean E, Kirby, Dean A, Lahrichi, Sabine L, Corrigan, Anne, Vale, Wylie W, Rivier, Catherine L
• Format: Article
• Language: English
• Subjects: Adrenalectomy; Amino Acid Sequence; Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; Corticotropin-Releasing Hormone - antagonists & inhibitors; Corticotropin-Releasing Hormone - chemical synthesis; Corticotropin-Releasing Hormone - chemistry; Corticotropin-Releasing Hormone - pharmacology; Corticotropin-Releasing Hormone - secretion; Electrophoresis, Capillary; Hormones. Endocrine system; Humans; In Vitro Techniques; Male; Mass Spectrometry; Medical sciences; Molecular Sequence Data; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Pituitary Gland, Anterior - cytology; Pituitary Gland, Anterior - secretion; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9902133

In an earlier report we identified specific modifications and substitutions of corticotropin releasing factor (CRF) that led to the discovery of antagonists with extended duration of action as compared to that of astressin {cyclo(30−33)[dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(12 - 41)}. These additional modifications included elongation of the peptide chain by three residues at the N-terminus, its acetylation, and the [CαMeLeu27] substitution to yield cyclo(30−33)[dPhe12, Nle21,CαMeLeu27,Glu30,Lys33,Nle38]Ac-hCRF(9 - 41), which was found to be longer acting than astressin (Rivier, J.; et al. J. Med. Chem. 1998, 41, 5012−5019). To further increase the efficiency (potency, duration of action, and bioavailability) of this family of antagonists, we introduced two or more CαMe-leucine residues at positions shown in earlier studies to be favorable (Hernandez, J.-F.; et al. J. Med. Chem. 1993, 36, 2860−2867). Whereas the introduction of CαMe-leucine residues at positions 27 and either 18 (11), 37 (17), or 40 (19) resulted in dramatic increases in duration of inhibitory action in the adrenalectomized (adx) rat after intravenous injection, the same substitution at positions 27 and either 15 (7, 8), 17 (9), 19 (12, 13), or 41 (20) led to short acting analogues. Other substitutions by CαMeLeu at positions 27 and either 10 (4), 13 (5), 14 (6), 21 (14), 24 (15), 36 (16), or 38 (18) yielded analogues with duration of action intermediate between those mentioned above. Cyclo(30−33)[dPhe12, Nle21,CαMeLeu27,Glu30,Lys33,Nle38,CαMeLeu40]Ac-hCRF(9 - 41) (astressin B, 19) was one of the most efficacious analogues of this series (>4 h inhibition of ACTH secretion at 25 μg/adx rat). It was found to be even longer acting via subcutaneous administration in either an aqueous (>24 h inhibition of ACTH secretion at 100 μg/adx rat) or lipid milieu (DMSO/peanut oil, >24 h inhibition of ACTH secretion at 30 μg/adx rat) than after intravenous administration (