SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Abstract Herein we disclose SAR studies that led to a series of isoindolineureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase(NAMPT) inhibitors. Modification of the isoindolineand/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.