We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
We recently described the discovery of oxygenated n class="Chemical">N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENVinfection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
Authors: Robert Jordan; Olga V Nikolaeva; Lijuan Wang; Bertha Conyers; Anand Mehta; Raymond A Dwek; Timothy M Block Journal: Virology Date: 2002-03-30 Impact factor: 3.616
Authors: Anand Mehta; Serguey Ouzounov; Robert Jordan; Ender Simsek; Xuanyong Lu; Robert M Moriarty; Gary Jacob; Raymond A Dwek; Timothy M Block Journal: Antivir Chem Chemother Date: 2002-09
Authors: Jinhong Chang; Travis K Warren; Xuesen Zhao; Tina Gill; Fang Guo; Lijuan Wang; Mary Ann Comunale; Yanming Du; Dominic S Alonzi; Wenquan Yu; Hong Ye; Fei Liu; Ju-Tao Guo; Anand Mehta; Andrea Cuconati; Terry D Butters; Sina Bavari; Xiaodong Xu; Timothy M Block Journal: Antiviral Res Date: 2013-04-08 Impact factor: 5.970
Authors: Fang Guo; Xuesen Zhao; Tina Gill; Yan Zhou; Matthew Campagna; Lijuan Wang; Fei Liu; Pinghu Zhang; Laura DiPaolo; Yanming Du; Xiaodong Xu; Dong Jiang; Lai Wei; Andrea Cuconati; Timothy M Block; Ju-Tao Guo; Jinhong Chang Journal: Antiviral Res Date: 2014-04-30 Impact factor: 5.970
Authors: Andrew C Sayce; Dominic S Alonzi; Sarah S Killingbeck; Beatrice E Tyrrell; Michelle L Hill; Alessandro T Caputo; Ren Iwaki; Kyoko Kinami; Daisuke Ide; J L Kiappes; P Robert Beatty; Atsushi Kato; Eva Harris; Raymond A Dwek; Joanna L Miller; Nicole Zitzmann Journal: PLoS Negl Trop Dis Date: 2016-03-14
Authors: Xingxian Gu; Vijayalaxmi Gupta; Yan Yang; Jin-Yi Zhu; Erick J Carlson; Carolyn Kingsley; Joseph S Tash; Ernst Schönbrunn; Jon Hawkinson; Gunda I Georg Journal: ChemMedChem Date: 2017-11-24 Impact factor: 3.466