title: Synthesis of 3-[(2,3-dihydro-1,1,3-trioxo-1,2-benzisothiazol-2-yl)alkyl] 1,4-dihydropyridine-3,5-dicarboxylate derivatives as calcium channel modulators.
abstract: 1,4-Dihydropyridine (DHP) derivatives with a 1,2-benzisothiazol-3-one 1,1-dioxide group, linked through an alkylene bridge to the C-3 carboxylate of the DHP ring, with both vasoconstricting and vasorelaxant properties were obtained. In blocking Ca(2+)-evoked contractions of K(+)-depolarized rabbit aortic strips, compounds 12 and 41 were 10-fold more potent than nifedipine; 27 other compounds were 1-4-fold more potent. Their vascular versus cardiac selectivity was very pronounced; for instance, the selectivity index for compound 41 was 70-fold higher than that of nifedipine. This was also true for the vasoconstricting compound 22, which was as potent as Bay K 8644 in enhancing the Ca(2+)-evoked contractions of rabbit aorta strips, yet it had poor inotropic activity in rabbit left atria. Oral administration of compounds 38, 40, 43, and 53 (20 mg/kg) caused a 35-37% decrease in systolic blood pressure in spontaneously hypertensive rats (SHR); these effects were similar to those of nifedipine. However, iv administration of these compounds to anesthetized SHR caused a decrease in blood pressure which was more pronounced and long-lasting than that of nifedipine. When administered iv at 100 micrograms/kg, the vasoconstricting compound 22 caused a 40% increase in systolic and diastolic blood pressure. Compound 22 exhibited an unusually interesting feature over the other five Ca2+ DHP agonists: it had diester substitutions at the C-3 and C-5 positions of the DHP ring. Overall, compounds possessing these properties might be useful in treating clinical cardiovascular conditions in which DHP Ca2+ antagonists or agonists are indicated.
authors.affiliation: Alter, S.A., Research Department, Mateo Inurria, Madrid, Spain.
authors.forename: C E
authors.initials: CE
authors.lastname: Sunkel
authors.forename: M
authors.initials: M
authors.lastname: Fau de Casa-Juana
authors.forename: L
authors.initials: L
authors.lastname: Santos
authors.forename: A G
authors.initials: AG
authors.lastname: García
authors.forename: C R
authors.initials: CR
authors.lastname: Artalejo
authors.forename: M
authors.initials: M
authors.lastname: Villarroya
authors.forename: M A
authors.initials: MA
authors.lastname: González-Morales
authors.forename: M G
authors.initials: MG
authors.lastname: López
authors.forename: J
authors.initials: J
authors.lastname: Cillero
authors.forename: S
authors.initials: S
authors.lastname: Alonso
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D002412:Cations; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D002412:Cations; D004095:Dihydropyridines; D013844:Thiazoles; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011188:Potassium; D002118:Calcium