Bioorganic & Medicinal Chemistry Letters 2014-08-15

Discovery libraries targeting the major enzyme classes: the serine hydrolases.

Katerina Otrubova, Venkat Srinivasan, Dale L Boger

Index: Bioorg. Med. Chem. Lett. 24(16) , 3807-13, (2014)

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Abstract

Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent structural diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki=100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas.Copyright © 2014 Elsevier Ltd. All rights reserved.