MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats

Abstract Rational modification of the clinically tested CGRP receptor antagonist MK-3207 ( 3 ) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8 R )-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]- N -[(6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[ b ]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) ( 6 ). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.