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

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1502-1506. doi: 10.1016/j.bmcl.2019.04.013.

Kuojun Zhang ¹, Yong Ni ², Jiaxuan Chen ³, Zhengchao Tu ⁴, Xiaoxing Wu ³, Dong Chen ³, Hequan Yao ³, Sheng Jiang ⁵

Affiliations

1 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
2 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
4 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jiangsh9@gmail.com.

PMID: 30992165 DOI: 10.1016/j.bmcl.2019.04.013

Abstract

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 (IC₅₀ = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC₅₀ 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 IC₅₀ 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.

Keywords

Acrylamide; Anticancer; Antiproliferative activity; Biarylsulfanilamide; NAMPT inhibitor.

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