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Junwon Kim,
Doohyun Lee,
Changmin Park,
Wonyoung So, Mina Jo,
Taedong Ok,
Jeongjin Kwon,
Sunju Kong,
Suyeon Jo,
Youngmi Kim, [......],
Moon Kyeong Ju,
Junghwan Kim,
Sung-Jun Han,
Tae-Hee Kim,
Jonathan Cechetto,
Jiyoun Nam,
Peter Sommer,
Michel Liuzzi,
Jinhwa Lee,
Zaesung No
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ABSTRACT: We 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.
ACS Medicinal Chemistry Letters 07/2012; · 3.36 Impact Factor
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Junwon Kim,
Changmin Park,
Taedong Ok,
Wonyoung So, Mina Jo,
Minjung Seo,
Youngmi Kim,
Jeong-Hun Sohn,
Youngsam Park,
Moon Kyeong Ju,
Junghwan Kim,
Sung-Jun Han,
Tae-Hee Kim,
Jonathan Cechetto,
Jiyoun Nam,
Peter Sommer,
Zaesung No
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ABSTRACT: 3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) were selected and derivatized through a HIV-1 replication assay based on GFP reporter cells. Compounds 14, 25, 31, and 36 exhibited significant inhibition of HIV-1 replication with a good safety profile. Chiral separation of each enantiomer by fractional crystallization showed that only the S enantiomer retained anti-HIV activity. Compound (S)-40, a novel and potent DHPM analog, could serve as an advanced lead for further development and the determination of the mechanism of action.
Bioorganic & medicinal chemistry letters 03/2012; 22(5):2119-24. · 2.65 Impact Factor
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Junwon Kim,
Taedong Ok,
Changmin Park,
Wonyoung So, Mina Jo,
Youngmi Kim,
Minjung Seo,
Doohyun Lee,
Suyeon Jo,
Yoonae Ko, [......],
Moon Kyeong Ju,
JiYe Ahn,
Junghwan Kim,
Sung-Jun Han,
Tae-Hee Kim,
Jonathan Cechetto,
Jiyoun Nam,
Michel Liuzzi,
Peter Sommer,
Zaesung No
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ABSTRACT: Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.
Bioorganic & medicinal chemistry letters 02/2012; 22(7):2522-6. · 2.65 Impact Factor
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Tetrahedron Letters 50(11):1229-1235. · 2.68 Impact Factor
