Synthesis and calcium antagonistic activity of (+)-(R)- and (-)-(S)-3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5- trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline hydrochloride.
SA2572 ((+)-1), 3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl) amino] butoxy]phenyl]-benzothiazoline hydrochloride is a newly synthesized Ca2+ antagonist having a inhibitory effect on the fast Na+ inward channel. In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca2+ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca2+ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na+ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca2+ inward channel as compared with compound (-)-1. Stereoselectivity of the pharmacological activity was found.
Fujita
M
M
Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Ota
A
A
Ito
S
S
Yamamoto
K
K
Kawashima
Y
Y
Iso
T
T
Iwao
J
J
D000818:Animals; D052160:Benzothiazoles; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004594:Electrophysiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D013844:Thiazoles; C057199:SA 2572