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.
Pramod Joshi  1 ,  Corey Anderson  1 ,  Hayley Binch  1 ,  Sabine Hadida  1 ,  Sanghee Yoo  2 ,  Danielle Bergeron  2 ,  Caroline Decker  3 ,  Ernst terHaar  4 ,  Jonathan Moore  4 ,  Miguel Garcia-Guzman  5 ,  Andreas Termin  6
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: [email protected].
  • 6. Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: [email protected].
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.