| Literature DB >> 24900170 |
Ian M Bell1, Steven N Gallicchio1, Michael R Wood1, Amy G Quigley1, Craig A Stump1, C Blair Zartman1, John F Fay2, Chi-Chung Li3, Joseph J Lynch4, Eric L Moore5, Scott D Mosser2, Thomayant Prueksaritanont6, Christopher P Regan4, Shane Roller6, Christopher A Salvatore5, Stefanie A Kane5, Joseph P Vacca1, Harold G Selnick1.
Abstract
Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.Entities:
Keywords: MK-3207; calcitonin gene-related peptide; pharmacokinetics; receptor antagonist
Year: 2010 PMID： 24900170 PMCID： PMC4007836 DOI： 10.1021/ml900016y
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345