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

Authors

  • Olivier Bezençon Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland. olivier.bezencon@idorsia.com
  • Thomas Pfeifer Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Johannes Mosbacher Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Isabelle Reymond Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Eric A. Ertel Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Ruben de Kanter Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Bruno Capeleto Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Elvire Fournier Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Markus Rey Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Luca Moccia Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Michael Toeroek-Schafroth Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • René Roscher Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Richard Moon Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • John Gatfield Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Melanie Kessler Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Romain Siegrist Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Bibia Heidmann Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Davide Pozzi Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Simon Stamm Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Luboš Remeň Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Sylvia Richard Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Lloyd Simons Kalexsyn, Inc. 4502 Campus Drive, Kalamazoo, MI 49008, USA
  • Rick Gaston Kalexsyn, Inc. 4502 Campus Drive, Kalamazoo, MI 49008, USA
  • Dennis Downing Kalexsyn, Inc. 4502 Campus Drive, Kalamazoo, MI 49008, USA
  • Corinna Grisostomi Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Catherine Roch Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
  • Benno Schindelholz Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland

DOI:

https://doi.org/10.2533/chimia.2017.722

Keywords:

Absence epilepsy, Ames test, Lead optimization, T-type calcium channel blockers

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.
CHIMIA Vol. 71 No. 10 (2017): Medicinal Chemistry

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Published

2017-10-25

Issue

Vol. 71 No. 10 (2017): Medicinal Chemistry

Section

Scientific Articles

License

Copyright (c) 2017 Swiss Chemical Society

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

How to Cite

[1]
O. Bezençon, T. Pfeifer, J. Mosbacher, I. Reymond, E. A. Ertel, R. de Kanter, B. Capeleto, E. Fournier, M. Rey, L. Moccia, M. Toeroek-Schafroth, R. Roscher, R. Moon, J. Gatfield, M. Kessler, R. Siegrist, B. Heidmann, D. Pozzi, S. Stamm, L. Remeň, S. Richard, L. Simons, R. Gaston, D. Downing, C. Grisostomi, C. Roch, B. Schindelholz, Chimia 2017, 71, 722, DOI: 10.2533/chimia.2017.722.