Lipophilic 6-Halo-2′,3′-Dideoxypurine Nucleosides: Potential Antiretroviral Agents Targeting HIV-Associated Neurologic Disorders

Abstract

In the past seven years, a number of potentially useful approaches for the therapy of human immunodeficiency virus (HIV) infection have emerged.^1–3 One such approach is the use of the broad family of 2′,3′-dideoxynucleosides (ddN) as therapeutic agents.^4,5 3′-Azido-2′,3′dideoxythymidine (AZT or zidovudine), the first member of the dideoxynucleoside family administered to humans, has now been formally proven to reduce the morbidity and mortality of patients with acquired immunodeficiency syndrome (AIDS) and its related disorders.^6–8 AZT has also been proven to benefit certain asymptomatic individuals infected with HIV-1 when administered in the early stages of HIV infection.9 It is worth noting that AZT has most recently been hown to be active at lower doses than that initially ministered.10,11 Two other analogs of the dideoxynucleoside family, 2′,3′-dideoxycytidine (ddC)¹2,13 and 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T),¹⁴ have also demonstrated activity against HIV-1 in some patients in Phase I clinical trials. A purine member, 2′,3′-dideoxyinosine (ddI or didanosine), has also recently been shown to be active against HIV-1 in patients with AIDS and advanced AIDS related complex (ARC) in short-term Phase I clinical trials, although notable adverse effects including painful peripheral neuropathy and acute pancreatitis have been observed.^15–17 In this regard, certain doses of ddl which can confer antiviral effects on patients have been tolerated for more than 2 years without toxicity.¹⁸ ddI is now under phase II clinical trials in several countries.