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

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).