303   ACH-126,443: A New Nucleoside Analog with Potent Activity against Wild-Type and Resistant HIV-1 and a Promising Pharmacokinetic and Mitochondrial Safety Profile.

L. M. Dunkle*¹, S. C. Oshana¹, Y.-C. Cheng², K. Hertogs³, and W. G. Rice¹.
¹Achillion Pharmaceuticals, New Haven, CT;²Yale Univ., New Haven, CT; and³VIRCO Labs, Mechelen, Belgium.

Background:ACH-126,443 (b-L-Fd4C) is an L-nucleoside analog designed to improve on earlier analogs by providing potent anti-HIV and -HBV activity while avoiding mitochondrial toxicity. Early work with the compound demonstrated anti-HIV activity 10—20-fold greater than 3TC, excellent oral bioavailability in two species and an intracellular T_1/2exceeding 24 hours. In vitro studies showed no reduction in mitochondrial DNA following cellular exposure tob-L-Fd4C alone and amelioration of mitochondrial DNA loss due to d4T when the two drugs were combined.

Methods:Antiviral activity against wild-type (WT) HIV-1 and 65 clinical strains with known nucleoside (NRTI) resistance mutations at M41L, M184V, T215Y, and Q151M, 69S insert and NNRTI resistance mutations at K103N, Y181C and G190A was tested phenotypically, using a recombinant virus assay approach (Antivirogram, VIRCO). Genotypic analysis of the tested strains had been performed by VIRCO using ABI DNA sequencing. Control drugs included ZDV, ddI, d4T, ddC, 3TC, abacavir, efavirenz, nevirapine and delavirdine.

Results:b-L-Fd4C IC₅₀against WT was 0.1—0.3mM; IC₅₀against all mutant strains, except M184V, was unchanged from WT. IC₅₀against M184V mutants was 1—4mM, equivalent to that of 3TC against WT virus. IC₅₀of 3TC against the M184V mutants exceeded 30mM. No change in susceptibility tobL-Fd4C was conferred by any other NRTI mutations, including the multi-nucleoside resistance mutations, or by NNRTI mutations.

Conclusions:ACH-126,443 (b-L-Fd4C) is a nucleoside analog with exceptional anti-HIV potency, especially against strains resistant to other nucleosides. This broad range of potency, combined with very promising preclinical pharmacokinetic and mitochondrial safety profiles, suggests thatb-L-Fd4C may provide an important nucleoside component for combination antiretroviral regimens at all stages of disease.