title: Preparation of imidazoles as potent calcitonin gene-related peptide (CGRP) antagonists.
abstract: Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.
authors.affiliation: Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: george.tora@bms.com.
authors.forename: George
authors.initials: G
authors.lastname: Tora
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kostich
authors.forename: Carl D
authors.initials: CD
authors.lastname: Davis
authors.forename: Sokhom S
authors.initials: SS
authors.lastname: Pin
authors.forename: Richard
authors.initials: R
authors.lastname: Schartman
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Widmann
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D015363:Quinolones; D018015:Receptors, Calcitonin Gene-Related Peptide; C029899:imidazole
keywords: CGRP; CGRP receptor antagonists; Imidazoles; Migraine; Migraineurs