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 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.
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Authors | T Yamamoto, M Hori, I Watanabe, H Tsutsui, K Harada, S Ikeda, J Maruo, T Morita, H Ohtaka |
Journal | Chemical & pharmaceutical bulletin
(Chem Pharm Bull (Tokyo))
Vol. 46
Issue 11
Pg. 1716-23
(Nov 1998)
ISSN: 0009-2363 [Print] Japan |
PMID | 9845955
(Publication Type: Journal Article)
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Chemical References |
- Guanidines
- Sodium-Hydrogen Exchangers
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Topics |
- Animals
- Arrhythmias, Cardiac
(chemically induced, pathology)
- Blood Platelets
(drug effects, ultrastructure)
- Chemical Phenomena
- Chemistry, Physical
- Guanidines
(chemical synthesis, pharmacology)
- In Vitro Techniques
- Magnetic Resonance Spectroscopy
- Male
- Myocardial Reperfusion Injury
(pathology)
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Sodium-Hydrogen Exchangers
(antagonists & inhibitors)
- Structure-Activity Relationship
- Ventricular Fibrillation
(chemically induced, pathology)
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