ml300146q_si_001.pdf (279.88 kB)
Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
journal contribution
posted on 2012-08-09, 00:00 authored by Junwon Kim, Doohyun Lee, Changmin Park, Wonyoung So, Mina Jo, Taedong Ok, Jeongjin Kwon, Sunju Kong, Suyeon Jo, Youngmi Kim, Jihyun Choi, Hyoung
Cheul Kim, Yoonae Ko, Inhee Choi, Youngsam Park, Jaewan Yoon, Moon
Kyeong Ju, Junghwan Kim, Sung-Jun Han, Tae-Hee Kim, Jonathan Cechetto, Jiyoun Nam, Peter Sommer, Michel Liuzzi, Jinhwa Lee, Zaesung NoWe identified a novel class of aryl-substituted triazine
compounds as potent non-nucleoside reverse transcriptase inhibitors
(NNRTIs) during a high-throughput screening campaign that evaluated
more than 200000 compounds for antihuman immunodeficiency virus (HIV)
activity using a cell-based full replication assay. Herein, we disclose
the optimization of the antiviral activity in a cell-based assay system
leading to the discovery of compound 27, which possessed
excellent potency against wild-type HIV-1 (EC50 = 0.2 nM)
as well as viruses bearing Y181C and K103N resistance mutations in
the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed
the mode of action of this novel class of NNRTIs. Introduction of
a chloro functional group in the pyrazole moiety dramatically improved
hERG and CYP inhibition profiles, yielding highly promising leads
for further development.