4 & PRIME;-Ethynyl-2 & PRIME;-deoxy-2 & PRIME;-& beta;-fluoro-2-fluoroadenosine: A Highly Potent and Orally Available Clinical Candidate for the Treatment of HIV-1 Infection

2 & PRIME;-Deoxy-2 & PRIME;-& beta;-fluoroadenosines bearing4 & PRIME;-azidoor 4 & PRIME;-ethynyl groups designed for the treatment of HIV-1 infectionhave been synthesized. All these compounds possess nanomolar anti-HIV-1activity, with the 4 & PRIME;-ethynyl-2-fluoroadenosine analog 1c (CL-197) being the most potent compound withlow cytotoxicity (EC50 = 0.9 nM, CC50 > 100 & mu;M). It also shows potent inhibitory activities on drug resistantand 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 targetcells, where the resulting triphosphate exhibited a long-term intracellularretention and could prevent HIV-1 infection for an extended time. 1c displayed low in vivo toxicity and favorablepharmacokinetics profiles in Sprague-Dawley rats. The preclinicaldata support further development of 1c as a highly potentand orally bioavailable clinical candidate to treat HIV-1 infection.Currently, CL-197 is in clinical trials in China (registrationnumber: CXHL2200529).