Q4 · MEDICINE
Article
Author: Doherty, George A ; Soni, Nirupama B ; Kovar, Peter J ; Buchanan, F Greg ; Frey, Robin R ; Longenecker, Kenton L ; Maag, David ; Tu, Noah ; Badagnani, Ilaria ; Sarris, Kathy A ; Cheng, Min ; Sorensen, Bryan K ; Guo, Jun ; Wilsbacher, Julie L ; Aguirre, Ana L ; Woller, Kevin ; Shrestha, Anurupa ; Pliushchev, Marina A ; Hansen, T Matthew ; Richardson, Paul L ; Curtin, Michael L ; Clark, Richard F ; Chiang, Gary G ; Algire, Mikkel A ; Raich, Diana ; Vasudevan, Anil ; Tse, Chris ; Marin, Violeta L ; Heyman, H Robin ; Michaelides, Michael R ; Korepanova, Alla V ; Cheng, Dong ; Sweis, Ramzi F
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/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.