4'-Ethynyl-2'-deoxy-2'-β-fluoro-2-fluoroadenosine: A Highly Potent and Orally Available Clinical Candidate for the Treatment of HIV-1 Infection

  • J Med Chem. 2023 Aug 24;66(16):11282-11293. doi: 10.1021/acs.jmedchem.3c00761.
Jiao Hou  1 ,  Youmei Peng  2 ,  Bingjie Liu  3 ,  Qianqian Zhang  1 ,  Jian-Hua Wang  4 ,  Wenquan Yu  1 ,  Junbiao Chang  1  4  3
Affiliations
  • 1. Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
  • 2. Henan Key Laboratory for Pharmacology of Liver Diseases, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
  • 3. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4. Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang 453007, China.
PMID: 37535016 DOI: 10.1021/acs.jmedchem.3c00761
Abstract

2'-Deoxy-2'-β-fluoroadenosines bearing 4'-azido or 4'-ethynyl groups designed for the treatment of HIV-1 Infection have been synthesized. All these compounds possess nanomolar anti-HIV-1 activity, with the 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197) being the most potent compound with low cytotoxicity (EC50 = 0.9 nM, CC50 > 100 μM). It also shows potent inhibitory activities on drug resistant and clinical HIV-1 strains. Oral administration of 1c to Beagle dogs resulted in high levels of its bioactive form 1c-TP in peripheral blood mononuclear cells, the HIV-1 target cells, where the resulting triphosphate exhibited a long-term intracellular retention and could prevent HIV-1 Infection for an extended time. 1c displayed low in vivo toxicity and favorable pharmacokinetics profiles in Sprague-Dawley rats. The preclinical data support further development of 1c as a highly potent and orally bioavailable clinical candidate to treat HIV-1 Infection. Currently, CL-197 is in clinical trials in China (registration number: CXHL2200529).

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