Fragment-Based Identification of Amides Derived from trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

• Published in: Journal of medicinal chemistry 2014-02, Vol.57 (3), p.770-792
• Main Authors: Giannetti, Anthony M, Zheng, Xiaozhang, Skelton, Nicholas J, Wang, Weiru, Bravo, Brandon J, Bair, Kenneth W, Baumeister, Timm, Cheng, Eric, Crocker, Lisa, Feng, Yezhen, Gunzner-Toste, Janet, Ho, Yen-Ching, Hua, Rongbao, Liederer, Bianca M, Liu, Yongbo, Ma, Xiaolei, O’Brien, Thomas, Oeh, Jason, Sampath, Deepak, Shen, Youming, Wang, Chengcheng, Wang, Leslie, Wu, Hongxing, Xiao, Yang, Yuen, Po-wai, Zak, Mark, Zhao, Guiling, Zhao, Qiang, Dragovich, Peter S
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Crystallography, X-Ray; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Drug Screening Assays, Antitumor; Heterografts; Humans; Mice; Mice, Nude; Models, Molecular; Neoplasm Transplantation; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Protein Conformation; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4015108

Potent, trans-2-(pyridin-3-yl)cyclopropane­carboxamide-containing inhibitors of the human nicotinamide phosphoribosyl­transferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, K D = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.