1. SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
- Author
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Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, and Michaelides MR
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Cytokines chemistry, Cytokines metabolism, Drug Discovery, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, Humans, Isoindoles chemistry, Isoindoles pharmacokinetics, Isoindoles pharmacology, Isoindoles therapeutic use, Mice, Models, Molecular, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Nicotinamide Phosphoribosyltransferase chemistry, Nicotinamide Phosphoribosyltransferase metabolism, Structure-Activity Relationship, Urea pharmacokinetics, Urea therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cytokines antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors, Urea analogs & derivatives, Urea pharmacology
- 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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