Preclinical and Clinical Profile of HIV-1 Integrase Strand-transfer Inhibitor GS-9224 Compared to its Parent Compound GS-9160
Gregg S Jones, Rebecca Hluhanich, Lani M Wieman, Jim Zheng, Wayne Huang, April Kinkade, Eugene J Eisenberg, Chris Yang, Damian McColl, Anita Mathias, Haolun Jin, Tomas Cihlar, Matthew Wright, Romas Geleziunas and Manuel Tsiang*
Gilead Sciences, Foster City, CA 94404, USA
- *Corresponding Author:
- Manuel Tsiang
Gilead Sciences, 333 Lakeside Drive
Foster City, CA 94404, USA
Tel: (650) 522-5860
Fax: (650) 522-5143
E-mail: [email protected]
Received Date: June 04, 2014; Accepted Date: July 10, 2014; Published Date: July 18, 2014
Citation: Jones GS, Hluhanich R, Wieman LM, Zheng J, Huang W, et al. (2014) Preclinical and Clinical Profile of HIV-1 Integrase Strand-transfer Inhibitor GS-9224 Compared to its Parent Compound GS-9160. J Antivir Antiretrovir 6:075-083. doi: 10.4172/jaa.10000101
Copyright: © 2014 Jones GS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In an effort to optimize the pharmacokinetic profile of GS-9160, a potent (EC50=1.2 – 4 nM) antiviral tri-cyclic
HIV-1 integrase (IN) strand transfer inhibitor (INSTI), various substitutions on the p-fluorobenzyl moiety of GS-9160
were explored. This effort led to the discovery of GS-9224, an analog containing a 5-chloro-2,4-di-fluorobenzyl
moiety. GS-9224, like its predecessor GS-9160, has potent (EC50=1.3 – 9 nM) and selective antiviral activity against
HIV-1 and acts as a bona fide integration inhibitor through elevation of 2-long terminal repeat (2-LTR) circles and
decrease of integration junctions in HIV-1 infected cells, markers of failed viral integration. Viral resistance selections
with GS-9224 yielded three mutations within the catalytic core domain of HIV-1 IN: G140S, L74M and Q148K.
When tested against a panel of HIV-1 clones engineered to express INSTI resistance mutations, the profile of
GS-9224 was comparable to GS-9160. GS-9224 exhibits improved hepatic microsome stability, better absorption
potential and a lower in vitro intestinal efflux ratio compared to GS-9160. In addition, GS-9224 displayed higher
dog plasma protein binding (~99%) than GS-9160 (~93%) suggesting a potential for protein restricted clearance.
However, the improved metabolic stability, absorption potential and serum protein binding of GS-9224 compared
to GS-9160 did not translate into an improved clinical pharmacokinetic profile. Results from a single-dose study in
human healthy subjects revealed a fast systemic clearance of GS-9224 with a terminal half-life of ~ 1 h, resulting in
a pharmacokinetic profile that would not support once-daily dosing in HIV-infected patients.