Caprolactams as potent CGRP receptor antagonists for the treatment of migraine
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Published on: August 11, 2021
Anthony W Shaw1, Daniel V Paone, Diem N Nguyen
1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. anthony_shaw@merck.com
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 (3R)-amino-(6S)-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%).
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