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.
Authors: Michael L Curtin, H Robin Heyman, Richard F Clark, Bryan K Sorensen, George A Doherty, T Matthew Hansen, Robin R Frey, Kathy A Sarris, Ana L Aguirre, Anurupa Shrestha, Noah Tu, Kevin Woller, Marina A Pliushchev, Ramzi F Sweis, Min Cheng, Julie L Wilsbacher, Peter J Kovar, Jun Guo, Dong Cheng, Kenton L Longenecker, Diana Raich, Alla V Korepanova, Nirupama B Soni, Mikkel A Algire, Paul L Richardson, Violeta L Marin, Ilaria Badagnani, Anil Vasudevan, F Greg Buchanan, David Maag, Gary G Chiang, Chris Tse, Michael R Michaelides