Journal of Medicinal Chemistry p. 10206 - 10217 (2018)
Update date:2022-08-03
Topics:
Credille, Cy V.
Dick, Benjamin L.
Morrison, Christine N.
Stokes, Ryjul W.
Adamek, Rebecca N.
Wu, Nicholas C.
Wilson, Ian A.
Cohen, Seth M.
Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values <50 nM. This SAR led to structurally distinct molecules that also displayed IC50 values of ~10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.
View MoreHuangshi Shennong Chemical Technology Co., Ltd
Contact:+86-714-3072290
Address:Eastern industrial park , Tieshan district , Huangshi city ,Hubei province , China
Neworld Chemical Co., Ltd Shanghai(expird)
Contact:+86-21-62202658
Address:11F, Blvd 2, No. 1969 PuXing Rd, Shanghai
Tianjin Jiuri New Materials Co., Ltd.
Contact:+86-22-58889220
Address:C-5/6, Vison Hill, No.1 Gonghua Road, Huayuan Hi-tech Park, Tianjin, China.
Shanghai He Yang International Trading Co., Ltd.
Contact:+86-21-52043598
Address:Room 816, Blag.5, No.58 Huachi Road
Refine Chemicals Science & Technology Technology Developing Co., Ltd.
Contact:+86-22-87899130
Address:No.12,west keyan road,Tianjin City
Doi:10.1002/anie.200250644
(2003)Doi:10.1016/S0022-1139(00)82100-4
(1976)Doi:10.1016/S0960-894X(03)00431-1
(2003)Doi:10.1002/hlca.193401701171
(1934)Doi:10.1021/ol034823f
(2003)Doi:10.1016/S0008-6215(03)00181-2
(2003)