Conformational study of 2-phenylbenzothiazine part of SA2995, a Ca2+ antagonist having a benzothiazine skeleton, and structure-activity relationships.
Nuclear magnetic resonance (NMR) studies were carried out for the title compound ((+/-)-3,4-dihydro-2-[5-methoxy-2- [3-[N-methyl-N-[2-(3,4-methylenedioxy)phenoxy]ethyl]amino] propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine) (1a; R = H) and its 2-substituted analogs (1b; R = OCH3, 1c; R = SCH3, 1d; R = CH3, 1e; R = i-C3H7) which had Ca2+ antagonistic activities. Conformational analysis using the model compounds of the 2-phenylbenzothiazine (2-PBT) part of 1 by semiempirical molecular orbital method agreed with the NMR behavior. Two local minimum conformations, having different rotational angles (theta 1) of the 2-phenyl ring, were suggested for biologically active 1a-1d. The molar fractional ratios, including the conformations within a particular theta 1 range that contained each global minimum conformation, were found to correlate well with the activities. In the same theta 1 range, any stable conformation was not indicated for non-active compound 1e. From these results, the active conformation for the 2-PBT part of 1 was suggested to be similar to the global minimum conformation indicated for the most potent 1a.
Fujimura
K
K
Developmental Research Laboratories, Santen Pharmaceutical, Co., Ltd., Osaka, Japan.
Fujita
M
M
Suhara
H
H
Kawashima
Y
Y
D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D002432:Cecum / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D013844:Thiazoles; C064356:sesamodil