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Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist.

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.

SUBMITTER: Bell IM

PROVIDER: S-EPMC4007836 | biostudies-other | 2010 Apr

REPOSITORIES: biostudies-other

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Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist.

Bell Ian M IM Gallicchio Steven N SN Wood Michael R MR Quigley Amy G AG Stump Craig A CA Zartman C Blair CB Fay John F JF Li Chi-Chung CC Lynch Joseph J JJ Moore Eric L EL Mosser Scott D SD Prueksaritanont Thomayant T Regan Christopher P CP Roller Shane S Salvatore Christopher A CA Kane Stefanie A SA Vacca Joseph P JP Selnick Harold G HG

ACS medicinal chemistry letters 20100112 1

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-tetrahydrospir ...[more]

PMID: 24900170

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