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

[Display omitted] 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 pro...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (15), p.3317-3325
Main Authors: Curtin, Michael L., Heyman, H. Robin, Clark, Richard F., Sorensen, Bryan K., Doherty, George A., Hansen, T. Matthew, Frey, Robin R., Sarris, Kathy A., Aguirre, Ana L., Shrestha, Anurupa, Tu, Noah, Woller, Kevin, Pliushchev, Marina A., Sweis, Ramzi F., Cheng, Min, Wilsbacher, Julie L., Kovar, Peter J., Guo, Jun, Cheng, Dong, Longenecker, Kenton L., Raich, Diana, Korepanova, Alla V., Soni, Nirupama B., Algire, Mikkel A., Richardson, Paul L., Marin, Violeta L., Badagnani, Ilaria, Vasudevan, Anil, Buchanan, F. Greg, Maag, David, Chiang, Gary G., Tse, Chris, Michaelides, Michael R.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antitumor activity
BASIC BIOLOGICAL SCIENCES
Cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Crystallography, X-Ray
Cytokines - antagonists & inhibitors
Cytokines - chemistry
Cytokines - metabolism
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Humans
Isoindoles - chemistry
Isoindoles - pharmacokinetics
Isoindoles - pharmacology
Isoindoles - therapeutic use
Isoindoline ureas
Mice
Models, Molecular
NAMPT inhibitors
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase - chemistry
Nicotinamide Phosphoribosyltransferase - metabolism
Structure-Activity Relationship
Urea - analogs & derivatives
Urea - pharmacokinetics
Urea - pharmacology
Urea - therapeutic use
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.06.018