title: The discovery of highly potent CGRP receptor antagonists.
abstract: Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co, Inc, West Point, PA 19486, USA. craig_stump@merck.com
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Cory R
authors.initials: CR
authors.lastname: Theberge
authors.forename: C
authors.initials: C
authors.lastname: Blair 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; D000818:Animals; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008253:Macaca mulatta; D000078183:Oxindoles; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C022960:2-oxindole