Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles

  • J Med Chem. 2019 Dec 26;62(24):11430-11436. doi: 10.1021/acs.jmedchem.9b01446.
Yali Sang  1  2 ,  Sheng Han  1  2 ,  Christophe Pannecouque  3 ,  Erik De Clercq  3 ,  Chunlin Zhuang  1  2 ,  Fener Chen  1  2  4
Affiliations
  • 1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry , Fudan University , Shanghai 200433 , People's Republic of China.
  • 2. Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , Shanghai 200433 , People's Republic of China.
  • 3. Rega Institute for Medical Research , KU Leuven , Herestraat 49 , B-3000 Leuven , Belgium.
  • 4. Institute of Pharmaceutical Science and Technology , Zhejiang University of Technology , 18 Chao Wang Road , 310014 Hangzhou , China.
PMID: 31714780 DOI: 10.1021/acs.jmedchem.9b01446
Abstract

A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest Antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 μg/mL compared with ETR (≪1 μg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.