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JTK-303/GS 9137, a Novel Small-molecule Inhibitor of HIV-1 Integrase: Anti-HIV Activity Profile and Pharmacokinetics in Animals
Yuji Matsuzaki*1, W Watanabe1, K Yamataka1, M Sato1, S Enya1, M Kano1, E Kodama2, M Matsuoka2, and S Ikeda1
1Japan Tobacco, Osaka and 2Inst for Virus Res, Kyoto Univ, Japan
Background: HIV integrase (IN)
is an attractive target for anti-HIV therapy. JTK-303/GS9137 is a low molecular
weight HIV-1 IN inhibitor, which was discovered through screening with
recombinant HIV-1 IN.
Methods: Inhibitory activity against HIV-1 IN was evaluated
by microtitre plate assay using recombinant HIV-1 IN
(NL4-3) and short DNA oligonucleotides. Anti-HIV-1
activity was profiled using different cell types and several T-tropic and
M-tropic HIV-1. We used CEM-SS cells and HIV-1IIIB to evaluate in
vitro combination anti-HIV-1 activity of JTK-303 with 6 approved anti-HIV
drugs. Pharmacokinetic parameters were determined in rats and dogs.
Results: JTK-303 inhibited the DNA strand transfer
activity of HIV-1 IN with an IC50 of 8.8 nM. This activity was approximately 3-fold more
potent than L-870810. JTK-303 inhibited HIV-1IIIB replication in
human peripheral blood mononuclear cells (PBMC) in the absence or presence of
50% human serum with mean EC90 values of 1.2 and 9.8 nM, respectively. JTK-303 also inhibited replication of
HIV-1 clinical isolates, including 8 subtypes (A, B, C, D, E, F, G, O) and 8 drug-resistant viruses, with EC50
ranging from 0.02 to 1.26 nM. JTK-303 exhibited
synergistic (lamivudine [3TC], 3TC/zidovudine [AZT])
or additive (AZT, tenofovir [TDF], TDF/3TC, efavirenz [EFV], indinavir [IDV],
nelfinavir [NFV]) interactions in in
vitro combination studies. Bioavailability and total body clearance of
JTK-303 was 34.1 and 29.6%, and 0.5 and 1.0 L/hour/kg in
non-fasting rats and dogs, respectively.
Conclusions: JTK-303 is an HIV-1 IN strand transfer
inhibitor with potent anti-HIV-1 activity in vitro and good oral availability
in preclinical species.
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