biostudies-other00500Unknown1(1)Bell IMACS medicinal chemistry letters24-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC4007836Incorporation 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.biostudies-otherPMC4007836Europe PMCVacca JPGallicchio SNMosser SDStump CAWood MRMoore ELZartman CBSalvatore CARegan CPSelnick HGKane SABell IMLynch JJQuigley AGLi CCPrueksaritanont TRoller SFay JF50falseDiscovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist.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.2010-01-01T00:00:00Z2010 Apr2019-03-27T01:27:30Z2019-03-27T01:27:30ZS-EPMC40078362490017010.1021/ml900016y