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2004
Enzyme inhibiting activity
X 0220
Oxyguanidines. Part 2. Discovery of a Novel Orally Active Thrombin Inhibitor
Structure-Based Drug Design and Parallel Synthesis. — A combined
47- 218 Through
approach consisting of structure-based drug design and parallel synthesis leads to the
discovery of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as
guanidine bioisosteres. A solution-phase library of oxyguanidine analogues is prepared
in multi-milligram quantities either from 3,5-dichlorophenol in eleven steps or from
3-hydroxy-5-methylbenzoic acid in eight steps. In general, nonpolar alkyl chains and
smaller aromatic, heterocyclic or cycloalkyl rings on the nitrogen in the left-side part
of the oxoguanidines lead to the most potent compounds. Additionally, introduction of
a cyclopropyl group in the S1 binding pocket increases the potency about 2-3 fold (I).
The inhibitors are Caco-2 monolayer permeable. — (LU*, T.; et al.; Bioorg. Med.
Chem. Lett. 14 (2004) 14, 3727-3731; 3-Dimens. Pharm., Inc., Exton, PA 19341,
USA; Eng.) — H. Hoennerscheid
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