Synthesis and quantitative structure-activity relationships of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines as Na/H exchange inhibitors.
N-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines 4 were prepared and tested for Na/H exchange inhibitory activities in order to clarify the structure-activity relationship (SAR). Quantitative SAR (QSAR) analysis of 6-carbonylguanidines 4 indicated that the length of the 4-substituent was parabolically related to activity and that the calculated optimum 4-substituents were propyl, ethyl and isopropyl groups. This SAR was similar to the SAR of the 2- and 4-substituents of 7-carbonylguanidine derivatives 3, although the position relative to the essential guanidinocarbonyl group was different. Larger 2-substituents, such as a phenyl group were unfavorable. The most potent derivative in this series was N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro- 2H-benzo[1,4]oxazine-6-carbonyl)guanidine 4 g, with an IC50 value of 0.12 microM. The methanesulfonate salt (KB-R9032) of 4g had excellent water-solubility and showed anti-arrhythmia activity against a rat acute myocardial infarction model. KB-R9032 was selected for further investigation as a therapy for ischemia-reperfusion induced injury.
Yamamoto
T
T
Product R & D Laboratory, Kanebo Ltd., Osaka, Japan.
Hori
M
M
Watanabe
I
I
Tsutsui
H
H
Harada
K
K
Ikeda
S
S
Maruo
J
J
Morita
T
T
Ohtaka
H
H
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000473:pathology
D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers