CHIMIA (Oct 2017)
Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies
- Olivier Bezençon,
- Thomas Pfeifer,
- Johannes Mosbacher,
- Isabelle Reymond,
- Eric A. Ertel,
- Ruben de Kanter,
- Bruno Capeleto,
- Elvire Fournier,
- Markus Rey,
- Luca Moccia,
- Michael Toeroek-Schafroth,
- René Roscher,
- Richard Moon,
- John Gatfield,
- Melanie Kessler,
- Romain Siegrist,
- Bibia Heidmann,
- Davide Pozzi,
- Simon Stamm,
- Luboš Remeň,
- Sylvia Richard,
- Lloyd Simons,
- Rick Gaston,
- Dennis Downing,
- Corinna Grisostomi,
- Catherine Roch,
- Benno Schindelholz
Affiliations
- Olivier Bezençon
- Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland. [email protected]
- 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
- Journal volume & issue
-
Vol. 71,
no. 10
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.
Keywords
