4WQ6

The crystal structure of human Nicotinamide phosphoribosyltransferase (NAMPT) in complex with N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-c]pyridine-2-carboxamide inhibitor (compound 21)

Summary for 4WQ6

• Entry DOI: 10.2210/pdb4wq6/pdb
• Descriptor: Nicotinamide phosphoribosyltransferase, N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-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: Nucleus : P43490
• Total number of polymer chains: 2
• Total formula weight: 115950.66

Authors

Li, D.,Wang, W. (deposition date: 2014-10-21, release date: 2015-02-11, Last modification date: 2023-09-27)

Primary citation

Zak, M.,Liederer, B.M.,Sampath, D.,Yuen, P.W.,Bair, K.W.,Baumeister, T.,Buckmelter, A.J.,Clodfelter, K.H.,Cheng, E.,Crocker, L.,Fu, B.,Han, B.,Li, G.,Ho, Y.C.,Lin, J.,Liu, X.,Ly, J.,O'Brien, T.,Reynolds, D.J.,Skelton, N.,Smith, C.C.,Tay, S.,Wang, W.,Wang, Z.,Xiao, Y.,Zhang, L.,Zhao, G.,Zheng, X.,Dragovich, P.S.
Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.
Bioorg.Med.Chem.Lett., 25:529-541, 2015

PubMed Abstract: Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.

PubMed: 25556090
DOI: 10.1016/j.bmcl.2014.12.026

Experimental method

X-RAY DIFFRACTION (1.72 Å)