title: Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors.
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.
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Junwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Doohyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Changmin
authors.initials: C
authors.lastname: Park
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Wonyoung
authors.initials: W
authors.lastname: So
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: Jo
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Taedong
authors.initials: T
authors.lastname: Ok
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jeongjin
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Sunju
authors.initials: S
authors.lastname: Kong
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Suyeon
authors.initials: S
authors.lastname: Jo
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Hyoung Cheul
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Yoonae
authors.initials: Y
authors.lastname: Ko
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Choi
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Youngsam
authors.initials: Y
authors.lastname: Park
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jaewan
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Moon Kyeong
authors.initials: MK
authors.lastname: Ju
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Junghwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea ; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University , 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cechetto
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Nam
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Peter
authors.initials: P
authors.lastname: Sommer
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
authors.affiliation: Medicinal Chemistry 2, Medicinal Chemistry 1, Medicinal Chemistry 3, Drug Biology Group, Screening Technology Platforms Group, DMPK Group, Cell Biology of Retroviruses Group, Early Discovery Program, and Late Discovery Program, Institut Pasteur Korea (IP-K) , Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Zaesung
authors.initials: Z
authors.lastname: No
keywords: HIV-1; X-ray crystal structure; non-nucleoside reverse transcriptase inhibitors; reverse transcriptase; synthesis