Caprolactams as potent CGRP receptor antagonists for the treatment of migraine.

Abstract 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 (3 R )-amino-(6 S )-phenyl caprolactam template. The phenylimidazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding ( K i  = 2 nM) and cAMP (IC 50  = 4 nM) assays and was orally bioavailable in rats (27%).