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 Ki = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP Ki = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.

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