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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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (15), p.3317-3325
Hauptverfasser: 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.
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Sprache:eng
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Zusammenfassung:[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