Journal of Medicinal Chemistry p. 1562 - 1576 (2019)
Update date:2022-08-17
Topics:
Hopper, Allen T.
Brockman, Adam
Wise, Andy
Gould, Julie
Barks, Jennifer
Radke, Joshua B.
Sibley, L. David
Zou, Yongmao
Thomas, Stephen
A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR (TgDHFR) relative to human DHFR (hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.
View MoreHubei Xinghuo Chemical Co., Ltd.,
Contact:13925817279 13907299441
Address:Xinghuo Fine Chemistry Industrial Park, Xiaochang County, Hubei Province, China
Huaihua Baohua Biotechnology Co.,Ltd
website:http://www.baochengchem.com
Contact:86-519-82698291
Address:HouYang chemical development zone,Jintan,Jiangsu,China (213200)
Suzhou CarbonWell Pharma-Tech Co., Ltd
Contact:Tel: + 86 (0)512-8898-1216; + 86-18606258602
Address:2358 Changan Road, Wujiang Scientific Innovation Park, Wujiang, Jiangsu Province, P. R. China 215200
SHANDONG CREDAGRI CHEMICAL CO., LTD.
Contact:+86-531-88872050
Address:ROOM 601A, BUILDING 2, SHUNTAI SQUARE, NO. 2000 SHUNHUA ROAD, HI-TECH DEVELOPMENT ZONE, JINAN, CHINA.
Jiacheng-Chem Enterprises Limited
Contact:86-571-86711508
Address:19 Floor, CIBC Holley International Building, No. 198,Wuxing Road, Hangzhou, China,310020
Doi:10.1016/j.cattod.2017.04.023
(2017)Doi:10.1063/1.102033
(1989)Doi:10.1039/c8cy01992d
(2019)Doi:10.1039/d0dt00594k
(2020)Doi:10.1039/d0nj05894g
(2021)Doi:10.1246/bcsj.50.1749
(1977)