title: Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.
abstract: A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Hochman
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Cynthia
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Cory R
authors.initials: CR
authors.lastname: Theberge
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.forename: Xu-Fang
authors.initials: XF
authors.lastname: Zhang
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D000284:Administration, Oral; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007668:Kidney; D008958:Models, Molecular; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006827:Hydantoins; D013141:Spiro Compounds