SYNTHESIS OF POTENT INHIBITORS OF HISTIDINOL DEHYDROGENASE

Novel inhibitors of histidinol dehydrogenase are described. The most p otent inhibitors, compounds 18 (K-i = 4.4 nM) and 19 (K-i* = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The el ectrophilic ketone 6 designed to bind to an active site nucleophile wa s a considerably weaker inhibitor (IC50 similar to 20 mu M). Copyright (C) 1996 Elsevier Science Ltd