Identification of potent, highly constrained CGRP receptor antagonists

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i) = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i) = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species. (C) 2010 Elsevier Ltd. All rights reserved.