Synthesis and Quantitative Structure-Activity Relationship of N-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-5-carbonyl)guanidines as Na/H Exchange Inhibitors

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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 unfovorable. 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 IC_<50> 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.
公益社団法人日本薬学会の論文
1998-11-15