4NLD

Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with BMS-791325 also known as (1aR,12bS)-8-cyclohexyl-n-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide and 2-(4-fluorophenyl)-n-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide

Summary for 4NLD

• Entry DOI: 10.2210/pdb4nld/pdb
• Descriptor: RNA-directed RNA polymerase, (1aR,12bS)-8-cyclohexyl-N-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide, 2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide, ... (6 entities in total)
• Functional Keywords: ns5b, polymerase, hcv, hepatitis c virus, fingers, palm, thumb, transferase/transferase inhibitor, polymerase/polymerase inhibitor, transferase-transferase inhibitor complex
• Biological source: Hepatitis C virus (HCV)
• Total number of polymer chains: 1
• Total formula weight: 66010.80

Authors

Sheriff, S. (deposition date: 2013-11-14, release date: 2014-03-19, Last modification date: 2024-04-03)

Primary citation

Gentles, R.G.,Ding, M.,Bender, J.A.,Bergstrom, C.P.,Grant-Young, K.,Hewawasam, P.,Hudyma, T.,Martin, S.,Nickel, A.,Regueiro-Ren, A.,Tu, Y.,Yang, Z.,Yeung, K.S.,Zheng, X.,Chao, S.,Sun, J.H.,Beno, B.R.,Camac, D.M.,Chang, C.H.,Gao, M.,Morin, P.E.,Sheriff, S.,Tredup, J.,Wan, J.,Witmer, M.R.,Xie, D.,Hanumegowda, U.,Knipe, J.,Mosure, K.,Santone, K.S.,Parker, D.D.,Zhuo, X.,Lemm, J.,Liu, M.,Pelosi, L.,Rigat, K.,Voss, S.,Wang, Y.,Wang, Y.K.,Colonno, R.J.,Gao, M.,Roberts, S.B.,Gao, Q.,Ng, A.,Meanwell, N.A.,Kadow, J.F.
Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.
J.Med.Chem., 57:1855-1879, 2014

PubMed Abstract: Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

PubMed: 24397558
DOI: 10.1021/jm4016894

Experimental method

X-RAY DIFFRACTION (2.75 Å)