Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.

Authors:
Yong Ni
Yong Ni
National University of Singapore
Singapore
Jiaxuan Chen
Jiaxuan Chen
Georgia Institute of Technology
United States
Zhengchao Tu
Zhengchao Tu
Guangzhou Institutes of Biomedicine and Health
Guangzhou | China
Xiaoxing Wu
Xiaoxing Wu
Brandeis University
United States
Dong Chen
Dong Chen
Huaihe Hospital of Henan University
Kaifeng | China
Hequan Yao
Hequan Yao
State Key Laboratory of Natural Medicines
Sheng Jiang
Sheng Jiang
Laboratory of Medicinal Chemistry

Bioorg Med Chem Lett 2019 Jun 8;29(12):1502-1506. Epub 2019 Apr 8.

State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.

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Source
http://dx.doi.org/10.1016/j.bmcl.2019.04.013DOI Listing
June 2019

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