title: 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.
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.affiliation: In Vitro Sciences.
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.affiliation: Clinical PK/PD.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Li
authors.affiliation: Central Pharmacology.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.affiliation: Pain/Migraine.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.affiliation: In Vitro Sciences.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.affiliation: Drug Metabolism.
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.affiliation: Central Pharmacology.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.affiliation: Drug Metabolism.
authors.forename: Shane
authors.initials: S
authors.lastname: Roller
authors.affiliation: Pain/Migraine.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.affiliation: Pain/Migraine.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
keywords: MK-3207; calcitonin gene-related peptide; pharmacokinetics; receptor antagonist