2. Academic Validation
  3. Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

  • J Med Chem. 2022 Feb 10;65(3):2122-2138. doi: 10.1021/acs.jmedchem.1c01676.
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, Leuven B-3000, Belgium.
  • 5 Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, 18 Chao Wang Road, Hangzhou 310014, China.
PMID: 35073089 DOI: 10.1021/acs.jmedchem.1c01676
Abstract

A series of novel heteroaromatic biphenyl-methyl-pyrimidine analogues were designed via hybridization of privileged structures of two HIV-1 inhibitors. Among them, compound 7a containing 4-pyridinyl-phenyl and methyl-pyrimidine fragments revealed excellent wild-type HIV-1 inhibitory activity with low cytotoxicity. 7a had favorable solubility and liver microsome stability; moreover, no apparent CYP enzymatic inhibitory activity or acute toxicity was observed. However, its inhibitory activity toward mutant strains and the pharmacokinetic (PK) profiles were still unsatisfactory. Further optimizations resulted in a highly potent compound 9d without methyl on the pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum activity (EC50 = 2.0-57 nM) of 9d against resistant strains was revealed. This compound also exhibited good solubility and safety profiles and a good PK profile with an oral bioavailability of 59% in rats. Collectively, these novel heteroaromatic dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.

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