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

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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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Keywords: ABSENCE EPILEPSY; AMES TEST; LEAD OPTIMIZATION; T-TYPE CALCIUM CHANNEL BLOCKERS

Document Type: Research Article

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

Publication date: October 1, 2017

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  • International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions

    CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.

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