Synthesis and biological activity of novel calcium channel blockers: 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters and 2,5-dihydro-4-methyl-2-phenyl-1,5-benzodiazepine-3-carboxylic acid esters.
2,5-Dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters, based on the structures of dihydropyridines and diltiazem, were synthesized from o-aminothiophenol and 2-(phenylmethylene)- 3-oxobutanoic acid esters. Biological evaluation in the potassium-depolarized rabbit aorta suggests that these compounds are calcium channel blockers. The in vitro activity was further confirmed by electrophysiological techniques. Structure-activity studies for the aromatic substitution showed that the 2-nitro derivative was the most potent (IC50 = 0.3 microM) compound in vitro while the ethyl ester was slightly better than the corresponding methyl ester. Replacement of sulfur with nitrogen atom provided 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1,5-benzodiazepine-3-carboxylic acid ethyl ester, which was only slightly less active than the corresponding benzothiazepine. Derivatization of the nitrogen in 2,5-dihydro-4-methyl- 2-(3-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid methyl ester with a (dimethylamino)ethyl group (present in diltiazem) provided 2,5-dihydro-5-[(dimethylamino)ethyl]- 4-methyl-2-(3-nitrophenyl)-1,5-benzo-thiazepine-3-carboxylic acid methyl ester, which was found to be equipotent to diltiazem in vitro. Radioligand binding studies using [3H]nitrendipine and [3H]diltiazem showed that the compound with the free nitrogen binds competitively into the dihydropyridine binding site while the molecule in which the nitrogen is alkylated with a (dimethylamino)ethyl group interacts competitively with both diltiazem and dihydropyridine binding sites. Our results therefore show that 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic ester is a good starting point for designing dihydropyridine as well as diltiazem mimics.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015220:Calcium Channels; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines; D004110:Diltiazem / Q000494:pharmacology; D006168:Guinea Pigs; D007473:Ion Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000187:drug effects; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002264:Carboxylic Acids; D004095:Dihydropyridines; D007473:Ion Channels; D011725:Pyridines; D011978:Receptors, Nicotinic; D013841:Thiazepines; D001569:Benzodiazepines; C038806:1,4-dihydropyridine; D004110:Diltiazem