HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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 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.
AuthorsT Yamamoto, M Hori, I Watanabe, H Tsutsui, K Harada, S Ikeda, J Maruo, T Morita, H Ohtaka
JournalChemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 46 Issue 11 Pg. 1716-23 (Nov 1998) ISSN: 0009-2363 [Print] Japan
PMID9845955 (Publication Type: Journal Article)
Chemical References
  • Guanidines
  • Sodium-Hydrogen Exchangers
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: