Discovery of zoniporide: A potent and selective sodium–hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectiv...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2001-03, Vol.11 (6), p.803-807
Main Authors: Guzman-Perez, Angel, Wester, Ronald T., Allen, Mary C., Brown, Janice A., Buchholz, Allan R., Cook, Ewell R., Day, Wesley W., Hamanaka, Ernest S., Kennedy, Scott P., Knight, Delvin R., Kowalczyk, Paul J., Marala, Ravi B., Mularski, Christian J., Novomisle, William A., Ruggeri, Roger B., Tracey, W.Ross, Hill, Roger J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiovascular system
Dogs
Guanidines - chemistry
Guanidines - pharmacokinetics
Guanidines - pharmacology
Injections, Intravenous
Medical sciences
Miscellaneous
Molecular Conformation
Pharmacology. Drug treatments
Protective Agents - pharmacokinetics
Protective Agents - pharmacology
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - pharmacology
Rats
Sodium-Hydrogen Exchangers - antagonists & inhibitors
Sodium-Hydrogen Exchangers - metabolism
Solubility
Water - chemistry
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Summary:Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule. The discovery, synthesis, and activities of NHE-1 inhibitor zoniporide (CP-597,396) are presented.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)00059-2