TY - JOUR AU - Bezençon, Olivier AU - Pfeifer, Thomas AU - Mosbacher, Johannes AU - Reymond, Isabelle AU - Ertel, Eric A. AU - de Kanter, Ruben AU - Capeleto, Bruno AU - Fournier, Elvire AU - Rey, Markus AU - Moccia, Luca AU - Toeroek-Schafroth, Michael AU - Roscher, René AU - Moon, Richard AU - Gatfield, John AU - Kessler, Melanie AU - Siegrist, Romain AU - Heidmann, Bibia AU - Pozzi, Davide AU - Stamm, Simon AU - Remeň, Luboš AU - Richard, Sylvia AU - Simons, Lloyd AU - Gaston, Rick AU - Downing, Dennis AU - Grisostomi, Corinna AU - Roch, Catherine AU - Schindelholz, Benno PY - 2017/10/25 Y2 - 2024/03/29 TI - Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies JF - CHIMIA JA - Chimia VL - 71 IS - 10 SE - Scientific Articles DO - 10.2533/chimia.2017.722 UR - https://www.chimia.ch/chimia/article/view/2017_722 SP - 722 AB - 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. ER -