title: Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists.
abstract: Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Pramod
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Hayley
authors.initials: H
authors.lastname: Binch
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hadida
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Bergeron
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Drug Metabolism and Pharmacokinetics, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Decker
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Structural Biology, 130 Waverly Street, Cambridge, MA 02139, United States.
authors.forename: Ernst
authors.initials: E
authors.lastname: terHaar
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Structural Biology, 130 Waverly Street, Cambridge, MA 02139, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moore
authors.affiliation: Aspyrian Therapeutics Inc., 11189 Sorrento Valley Rd, San Diego CA 92121, United States. Electronic address: Miguel_Guzman@aspyriantherapeutics.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Guzman
authors.affiliation: Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: andreas_termin@vrtx.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Termin
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000493:pharmacokinetics; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D008881:Migraine Disorders / Q000188:drug therapy; D015394:Molecular Structure; D008970:Molecular Weight; D010879:Piperazines; D011485:Protein Binding / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics; D052999:Quinazolinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000819:agonists*; D045162:Thiazolidinediones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001381:Azepines; D004151:Dipeptides; D007093:Imidazoles; D010879:Piperazines; D011799:Quinazolines; D052999:Quinazolinones; D018015:Receptors, Calcitonin Gene-Related Peptide; D045162:Thiazolidinediones; D014508:Urea; C525458:telcagepant; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant
keywords: CGRP antagonists; Migraine; Thiazolidinone