2. Academic Validation
  3. Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

  • J Med Chem. 2021 Jul 22;64(14):10297-10311. doi: 10.1021/acs.jmedchem.1c00708.
Li Ding 1 2 3,  Christophe Pannecouque 4,  Erik De Clercq 4,  Chunlin Zhuang 2 3,  Fen-Er Chen 1 2 3 5
Affiliations

Affiliations

  • 1 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 2 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 3 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 4 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
  • 5 Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, Hangzhou 310014, China.
PMID: 34197708 DOI: 10.1021/acs.jmedchem.1c00708
Abstract

A series of novel heteroaromatic-difluoro-biphenyl-diarylpyrimidines were designed as non-nucleoside anti-HIV inhibitors targeting Reverse Transcriptase by a fragment-based replacement strategy with the purpose of improving the druggability. Hopping five- or six-membered heterocycle groups on the biphenyl moiety as bioisosterism for intrinsically cyanophenyl gave 23 derivatives. All of these compounds possessed excellent HIV-1 inhibitory activity in the nanomolar range. Among them, 12g with a 4-pyridine group displayed excellent inhibitory activity toward WT and mutant HIV virus possessing significant selectivity. Moreover, this compound exhibited a decent improvement in druggability than etravirine and rilpivirine: (1) The hydrochloric acid salt of 12g exhibited significantly improved water solubility in different pH conditions. (2) 12g did not show apparent CYP enzymatic inhibitory activity or acute toxicity. (3) Excellent oral bioavailability was also revealed (F = 126%, rats) in 12g. Collectively, these novel heteroaromatic-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.

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