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Exploration of Potential Prodrugs of RWJ‐445167, an Oxyguanidine‐based Dual Inhibitor of Thrombin and Factor Xa
Author(s) -
Maryanoff Bruce E.,
McComsey David F.,
Costanzo Michael J.,
Yabut Stephen C.,
Lu Tianbao,
Player Mark R.,
Giardino Edward C.,
Damiano Bruce P.
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00408.x
Subject(s) - prodrug , thrombin , bioavailability , pharmacology , chemistry , guanidine , amidine , drug , combinatorial chemistry , biochemistry , stereochemistry , medicine , platelet , immunology
Compound 2 (RWJ‐445167; 3DP‐10017), a dual inhibitor of thrombin and factor Xa, was advanced into human clinical studies. However, its oral bioavailability in humans proved to be below acceptable limits. To address this issue, we explored a prodrug approach involving numerous guanidine derivatives. Prodrug candidates of classes A (carbamate derivatives), B (imidate derivatives), and C (alkyl and acyl derivatives), compounds 3–6, were synthesized and evaluated for anticoagulant activity at 2h after oral administration to rats. In comparison to the parent drug (2), little worthwhile improvement was observed for the prodrug candidates.