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 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.

DOI: 10.1016/j.bmcl.2017.06.018

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Cite this paper

@article{Curtin2017SARAC, title={SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).}, author={Michael Curtin and H Robin Heyman and Richard F. Clark and Bryan K Sorensen and George A Doherty and T Matthew Hansen and Robin R Frey and Kathy A Sarris and Ana L Aguirre and Anurupa Shrestha and Noah P. Tu and Kevin R Woller and Marina A Pliushchev and Ramzi Farah Sweis and Min Cheng and Julie L. Wilsbacher and Peter Kov{\'a}r and Jun Guo and Dong Cheng and Kenton L Longenecker and Diana Raich and Alla V. Korepanova and Nirupama B Soni and Mikkel A. Algire and Paul L. Richardson and Violeta L Marin and Ilaria Badagnani and Anil Vasudevan and Fritz G. Buchanan and David X. Maag and Gary G Chiang and Chris Tse and Michael Michaelides}, journal={Bioorganic & medicinal chemistry letters}, year={2017}, volume={27 15}, pages={3317-3325} }