The discovery of highly potent CGRP receptor antagonists

Abstract Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25 , CGRP K i  = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.