Rational Design of Non-Nucleoside, Potent, and Orally Bioavailable Adenosine Deaminase Inhibitors: Predicting Enzyme Conformational Change and Metabolism

Abstract

From metabolic considerations and prediction of an inhibitor-induced conformational change, novel adenosine deaminase (ADA) inhibitors with improved activities and oral bioavailability have been developed on the basis of our originally designed non-nucleoside ADA inhibitors. They demonstrated in vivo efficacy in models of inflammation and lymphoma. Furthermore, X-ray crystal structure analysis has revealed a novel induced fit to ADA.