Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

作者：Dragovich Peter S^*; Bair Kenneth W; Baumeister Timm; Ho Yen Ching; Liederer Bianca M; Liu Xiongcai; Liu Yongbo; O'Brien Thomas; Oeh Jason; Sampath Deepak; Skelton Nicholas; Wang Leslie; Wang Weiru; Wu Hongxing; Xiao Yang; Yuen Po wai; Zak Mark; Zhang Lei; Zheng Xiaozhang

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(17): 4875-4885.

DOI：10.1016/j.bmcl.2013.06.090

• Nicotinamide phosphoribosyltransferase
• NAMPT
• Aqueous solubility
• X-ray crystal structure
• Tumor metabolism

Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.

• 出版日期2013-9-1