| Literature DB >> 22607672 |
Ian M Bell1, Craig A Stump, Steven N Gallicchio, Donnette D Staas, C Blair Zartman, Eric L Moore, Nova Sain, Mark Urban, Joseph G Bruno, Amy Calamari, Amanda L Kemmerer, Scott D Mosser, Christine Fandozzi, Rebecca B White, Matthew M Zrada, Harold G Selnick, Samuel L Graham, Joseph P Vacca, Stefanie A Kane, Christopher A Salvatore.
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-[(8R)-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.Entities:
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Year: 2012 PMID： 22607672 DOI： 10.1016/j.bmcl.2012.04.105
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823