4KFP

Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived Ureas as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

Summary for 4KFP

• Entry DOI: 10.2210/pdb4kfp/pdb
• Descriptor: Nicotinamide phosphoribosyltransferase, N-(4-{[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]sulfonyl}benzyl)-2H-pyrrolo[3,4-c]pyridine-2-carboxamide, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): P43490
• Total number of polymer chains: 2
• Total formula weight: 115664.30

Authors

Dragovich, P.S.,Bair, K.W.,Baumeister, T.,Ho, Y.,Liederer, B.M.,Liu, X.,O'Brien, T.,Oeh, J.,Sampath, D.,Skelton, N.,Wang, L.,Wang, W.,Wu, H.,Xiao, Y.,Yuen, P.,Zak, M.,Zhang, L.,Zheng, X. (deposition date: 2013-04-27, release date: 2013-08-14, Last modification date: 2024-02-28)

Primary citation

Dragovich, P.S.,Bair, K.W.,Baumeister, T.,Ho, Y.C.,Liederer, B.M.,Liu, X.,Liu, Y.,O'Brien, T.,Oeh, J.,Sampath, D.,Skelton, N.,Wang, L.,Wang, W.,Wu, H.,Xiao, Y.,Yuen, P.W.,Zak, M.,Zhang, L.,Zheng, X.
Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Bioorg.Med.Chem.Lett., 23:4875-4885, 2013

PubMed Abstract: 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 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.

PubMed: 23899614
DOI: 10.1016/j.bmcl.2013.06.090

Experimental method

X-RAY DIFFRACTION (1.84 Å)