Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.

Abstract A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12 , a potent CGRP receptor antagonist ( K i  = 21 nM) with good oral bioavailability in three species.