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

Abstract

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 4g, with an IC50 value of 0.12 μm. 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.