Potent benzimidazolone-based CGRP receptor antagonists

The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.

Elaboration of the benzimidazolone core of spirohydantoin CGRP receptor antagonists is described.Figure optionsDownload as PowerPoint slide