title: Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine.
abstract: In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: brendan_crowley@merck.com.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Crowley
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Potteiger
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Melody A
authors.initials: MA
authors.lastname: McWherter
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Paone
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.affiliation: Department of In Vitro Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Chemistry Modeling and Informatics, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Culberson
authors.affiliation: Department of In Vivo Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Danziger
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.affiliation: Department of In Vitro Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kemmerer
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Menzel
authors.affiliation: Department of Pain & Migraine, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.affiliation: Department of In Vitro Pharmacology, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.affiliation: Department of Genetic Tox & Molecular Carcinogenesis, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Reddy
authors.affiliation: Department of Pharmacokinetics Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.affiliation: Department of Pain & Migraine, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.affiliation: Department of Pain & Migraine, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, WP14-2, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
mesh_terms: D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D023303:Oxazolidinones
keywords: CGRP; Class B GPCR; Migraine; Oxazolidinone; Scaffold hopping