title: Preparation, Antiepileptic Activity, and Cardiovascular Safety of Dihydropyrazoles as Brain-Penetrant T-Type Calcium Channel Blockers.
abstract: A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Lubos
authors: L
authors: Remen
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Olivier
authors: O
authors: Bezençon
authors: Kalexsyn, Inc. , 4502 Campus Drive, Kalamazoo, Michigan 49008, United States.
authors: Lloyd
authors: L
authors: Simons
authors: Kalexsyn, Inc. , 4502 Campus Drive, Kalamazoo, Michigan 49008, United States.
authors: Rick
authors: R
authors: Gaston
authors: Kalexsyn, Inc. , 4502 Campus Drive, Kalamazoo, Michigan 49008, United States.
authors: Dennis
authors: D
authors: Downing
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: John
authors: J
authors: Gatfield
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Catherine
authors: C
authors: Roch
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Melanie
authors: M
authors: Kessler
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Johannes
authors: J
authors: Mosbacher
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Thomas
authors: T
authors: Pfeifer
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Corinna
authors: C
authors: Grisostomi
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Markus
authors: M
authors: Rey
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Eric A
authors: EA
authors: Ertel
authors: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Richard
authors: R
authors: Moon
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017208:Rats, Wistar
chemical_list: D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011720:Pyrazoles