Synthesis and SAR of 6-substituted purine derivatives as novel selective positive inotropes

A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. T...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-11, Vol.35 (24), p.4509-4515
Main Authors: Press, J B, Falotico, R, Hajos, Z G, Sawyers, R A, Kanojia, R M, Williams, L, Haertlein, B, Kauffman, J A, Lakas-Weiss, C, Salata, J J
Format: Article
Language:English
Subjects:
Animals
Blood Pressure - drug effects
Cardiotonic Agents - chemical synthesis
Cardiotonic Agents - pharmacology
Dogs
Ferrets
Heart Rate - drug effects
Male
Mercaptopurine - analogs & derivatives
Mercaptopurine - chemical synthesis
Mercaptopurine - pharmacology
Molecular Structure
Myocardial Contraction - drug effects
Papillary Muscles - drug effects
Papillary Muscles - physiology
Piperazines - chemical synthesis
Piperazines - pharmacology
Purines - chemical synthesis
Purines - pharmacology
Sodium Channels - drug effects
Sodium Channels - physiology
Stimulation, Chemical
Structure-Activity Relationship
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Summary:A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.
ISSN:0022-2623
DOI:10.1021/jm00102a001