Structural highlights
FunctionNAMPT_HUMAN Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). Publication Abstract from PubMedPotent 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=11nM; PC-3 antiproliferative IC50=36nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50=10nM; A2780 antiproliferative IC50=7nM) in complex with the NAMPT protein was also determined. Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Dragovich PS, Bair KW, Baumeister T, Ho YC, Liederer BM, Liu X, Liu Y, O'Brien T, Oeh J, Sampath D, Skelton N, Wang L, Wang W, Wu H, Xiao Y, Yuen PW, Zak M, Zhang L, Zheng X Bioorg Med Chem Lett. 2013 Sep 1;23(17):4875-85. doi: 10.1016/j.bmcl.2013.06.090., Epub 2013 Jul 6. PMID:23899614[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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