ANNUAL REPORTS IN MEDICINAL CHEMISTRY—38 ISSN: 0065-7743
Among the pyrimidine containing NRTI's, MIV-310 (3'-deoxy-3'-fluorothymidine) (4) and emtricitabine (FTC) (5), an analog of lamivudine (3TC), continue in phase II / III clinical development (9,10). Although more potent than 3TC in cell culture, in clinical studies, emtricitabine shows loss of susceptibility to viruses containing the 184(M-V) mutation in RT, a feature in common with lamivudine (11).
The successful use of NNRTI's in the treatment of AIDS is well-documented (12). Efavirenz (6), a so-called second generation compound, established a new standard of care when it was employed with a combination of NRTI's clinically (13,14). Nevertheless, the development of resistance to the NNRTI's is a significant medical problem (14). Mutations in RTat residues 100 (L-l), 103 (K-N), 181 (Y-C), 190 (G-S) and 230 (M-L), singly or in combination, result in viruses that successfully evade all three of the currently approved agents (15-18). Efforts to uncover third generation compounds with clinically useful efficacy against these resistant strains continue apace. Quinazolinone analogs of 6 have been studied in detail (19). The most advanced of these, DPC-083, (7) is 3-7 fold more potent against clinical isolates harboring resistance mutations to efavirenz (20). DPC-083 was shown to be safe and effective in clinical trials, lowering virals loads in patients who previously failed therapy with nevirapine (61%) or efavirenz (39%) (21,22).
Another third generation compound in clinical trials, dapivirine (TMC-125, R165335) (8) has been shown effective in treating infected individuals harboring phenotypic NNRTI resistant virus (23). Recent clinical studies uncovered significant drug-drug interactions with 8, an auto-inducer of CYP3A4, and other HIV drugs that are inducers of both CYP3A4 and glucuronidation (24). A more potent analog, TMC-120 (R147681) (9), also in clinical trials, requires the selection of at least a double mutation in RT 181 (Y-C) + 188(Y-L) for the development of significant resistance (25). Capravine (AG1549, S-1153) 10, is effective against viruses containing the mutation in RT at residue 103(K-N). Temporarily withdrawn from clinical trials due to vasculitis in dogs, phase III studies have resumed in a treatment experienced patient population (26).
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