Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists

Pramod Joshi; Corey Anderson; Hayley Binch; Sabine Hadida; Sanghee Yoo; Danielle Bergeron; Caroline Decker; Ernst terHaar; Jonathan Moore; Miguel Garcia-Guzman; Andreas Termin

doi:10.1016/j.bmcl.2013.12.089

Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists

Bioorg Med Chem Lett. 2014 Feb 1;24(3):845-9. doi: 10.1016/j.bmcl.2013.12.089. Epub 2013 Dec 26.

Authors

Affiliations

¹ Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States.
² Vertex Pharmaceuticals Inc., Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
³ Vertex Pharmaceuticals Inc., Department of Drug Metabolism and Pharmacokinetics, 11010 Torreyana Road, San Diego, CA 92121, United States.
⁴ Vertex Pharmaceuticals Inc., Department of Structural Biology, 130 Waverly Street, Cambridge, MA 02139, United States.
⁵ Aspyrian Therapeutics Inc., 11189 Sorrento Valley Rd, San Diego CA 92121, United States. Electronic address: Miguel_Guzman@aspyriantherapeutics.com.
⁶ Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: andreas_termin@vrtx.com.

PMID: 24405707
DOI: 10.1016/j.bmcl.2013.12.089

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.

Keywords: CGRP antagonists; Migraine; Thiazolidinone.

MeSH terms

Animals
Azepines / chemistry
Azepines / pharmacokinetics
Calcitonin Gene-Related Peptide / metabolism
Dipeptides / chemistry*
Dipeptides / pharmacokinetics
Dipeptides / pharmacology*
Humans
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Inhibitory Concentration 50
Migraine Disorders / drug therapy
Molecular Structure
Molecular Weight
Piperazines
Protein Binding / drug effects
Quinazolines / chemistry
Quinazolines / pharmacokinetics
Quinazolinones / chemistry*
Quinazolinones / pharmacokinetics
Quinazolinones / pharmacology*
Rats
Receptors, Calcitonin Gene-Related Peptide / agonists*
Thiazolidinediones / chemistry*
Thiazolidinediones / pharmacokinetics
Thiazolidinediones / pharmacology*
Urea / analogs & derivatives*
Urea / chemistry
Urea / pharmacokinetics
Urea / pharmacology

Substances

Azepines
Dipeptides
Imidazoles
Piperazines
Quinazolines
Quinazolinones
Receptors, Calcitonin Gene-Related Peptide
Thiazolidinediones
Urea
telcagepant
Calcitonin Gene-Related Peptide
olcegepant