Caprolactams as potent CGRP receptor antagonists for the treatment of migraine

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the benzodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring scaffold, phenyl substitution at various positions afforded the potent (3R)-amino-(6S)-phenyl caprolactam template. The phenylimidazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding (Ki = 2 nM) and cAMP (IC50 = 4 nM) assays and was orally bioavailable in rats (27%).

A series of (3R)-amino-(6S)-phenyl caprolactams were identified as benzodiazepine replacements for an early lead structure 1. The syntheses and SAR studies leading to the discovery of 24 are described.Figure optionsDownload as PowerPoint slide