title: Structure-Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and in Vivo Studies of New Brain Penetrant Triple T-Type Calcium Channel Blockers.
abstract: Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Siegrist
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Gaël
authors.initials: G
authors.lastname: Jacob
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Caterina
authors.initials: C
authors.lastname: Torrisi
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Kilian
authors.initials: K
authors.lastname: Colas
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Braibant
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mawet
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Roch
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kessler
authors.forename: Richard
authors.initials: R
authors.lastname: Moon
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Corminboeuf
authors.affiliation: Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bezençon
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type