SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) PMID: 28610984

ADC Targets in Oncology

2026-04-10

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

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3317-3325. doi: 10.1016/j.bmcl.2017.06.018.

Michael L Curtin ¹ , H Robin Heyman ² , Richard F Clark ² , Bryan K Sorensen ² , George A Doherty ² , T Matthew Hansen ² , Robin R Frey ² , Kathy A Sarris ² , Ana L Aguirre ² , Anurupa Shrestha ² , Noah Tu ² , Kevin Woller ² , Marina A Pliushchev ² , Ramzi F Sweis ² , Min Cheng ² , Julie L Wilsbacher ² , Peter J Kovar ² , Jun Guo ² , Dong Cheng ² , Kenton L Longenecker ² , Diana Raich ² , Alla V Korepanova ² , Nirupama B Soni ² , Mikkel A Algire ² , Paul L Richardson ² , Violeta L Marin ² , Ilaria Badagnani ² , Anil Vasudevan ² , F Greg Buchanan ² , David Maag ² , Gary G Chiang ² , Chris Tse ² , Michael R Michaelides ²

Affiliations

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.

Keywords

Antitumor activity; Cancer; Isoindoline ureas; NAMPT inhibitors.