Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies

  • Chimia (Aarau). 2017 Oct 25;71(10):722-729. doi: 10.2533/chimia.2017.722.
Olivier Bezençon  1 ,  Romain Siegrist  2 ,  Bibia Heidmann  2 ,  Davide Pozzi  2 ,  Simon Stamm  2 ,  Luboš Remeň  2 ,  Sylvia Richard  2 ,  Lloyd Simons  3 ,  Rick Gaston  3 ,  Dennis Downing  3 ,  Corinna Grisostomi  2 ,  Catherine Roch  2 ,  Melanie Kessler  2 ,  John Gatfield  2 ,  Richard Moon  2 ,  Thomas Pfeifer  2 ,  Johannes Mosbacher  2 ,  Isabelle Reymond  2 ,  Eric A Ertel  2 ,  Ruben de Kanter  2 ,  Bruno Capeleto  2 ,  Elvire Fournier  2 ,  Markus Rey  2 ,  Luca Moccia  2 ,  Michael Toeroek-Schafroth  2 ,  René Roscher  2 ,  Benno Schindelholz  2
Affiliations
  • 1. Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil;, Email: [email protected].
  • 2. Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil.
  • 3. Kalexsyn, Inc. 4502 Campus Drive, Kalamazoo, MI 49008, USA.
PMID: 29070417 DOI: 10.2533/chimia.2017.722
Abstract

We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.

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