Novel calcium antagonists. Synthesis and structure-activity relationship studies of benzothiazoline derivatives.
A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic activity than the corresponding thiazolidine derivatives (2). Effects of substituents R1-R4, the substitution position of the aminoalkoxy group and R2, and the length of the methylene chain on biological activities were examined. Compound 4 [3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl ) amino]butoxy]phenyl]benzothiazoline hydrochloride] showed a potent Ca2+ antagonistic activity in vitro and dual inhibition on the fast Na+ inward channel and the slow Ca2+ inward channel in Langendorff perfused rabbit hearts. Compound 4 also showed a long-acting hypotensive effect in spontaneously hypertensive rats and prevented acute pulmonary thrombotic death in mice.
Yamamoto
K
K
Research Laboratory, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Fujita
M
M
Tabashi
K
K
Kawashima
Y
Y
Kato
E
E
Oya
M
M
Iso
T
T
Iwao
J
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011655:Pulmonary Embolism / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D013844:Thiazoles