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

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 (EC 50 = 0.9 nM, CC 50 > 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).

Rational Molecular Editing: A New Paradigm in Drug Discovery

“… Azvudine (also known as FNC) was approved by NMPA for HIV and COVID-19 treatment . 4′-Ethynyl-2-fluoroadenosine ( CL-197 ) represents another highly potent and orally bioavailable nucleoside-based clinical candidate to treat HIV-1 infection (registration number: CXHL2200529) . It is important to note that installing the 4′-azido and 4′-ethynyl groups involves a multi-step synthetic process and falls under conventional structural modifications in design strategy.…”