17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

HIGHLY POTENT HIV PROTEASE INHIBITORS WITH SUBSTITUTED OXINDOLES IN P2′

Antivir Ther. 2008; 13(Suppl. 3):A35 (abstract no. 33)

SV Gulnik, EI Afonina, H Yokoe, B Yu, T Guerassina, AM Silva, JW Erickson and M Eissenstat
Sequoia Pharmaceuticals, Inc., Gaithersburg, MD, USA

BACKGROUND: HIV protease inhibitors (PIs) are effective antiretrovirals and one of the major components of highly active antiretroviral therapy regimens. In spite of their success, viral resistance, toxic side effects and suboptimal pharmacokinetic properties of these drugs remain major issues. Therefore, there is a persistent clinical need for discovery and development of potent and broad-spectrum PIs with reduced toxicity for the treatment of multidrug resistant (MDR) HIV strains.

METHODS: We have implemented a structure-based approach for the design of novel PIs with enaminooxindole substituents in the P2′ position. The potency of these inhibitors was evaluated against wild type (WT) and MDR mutant forms of HIV protease (PR) in an enzyme- based assay using a fluorogenic substrate and in a cell- based antiviral assay in MT4 cells. The crystallographic structures of representative inhibitors in complex with HIV PR were determined to support the structure activity relationship data.

RESULTS: We designed and synthesized a series of HIV PIs with an enamino-oxindole in P2′. Several inhibitors of this series were comparable to or, in some instances, superior to darunavir in in vitro enzyme-based and cell-based assays. The best compounds have subnanomolar K_is and antiviral IC₅₀s in the low nanomolar range against WT HIV and retain activity against a panel of eight MDR strains. For example, a tert-butylmethyl substituted analogue exhibited antiviral IC₅₀ of 4.5 nM against WT and average IC₅₀ of 10.1 nM (range 1.5–27 nM) against mutant viruses with average fold change (FC) of 2.3 (range 0.3–6). For comparison, darunavir has antiviral IC₅₀ of 4.7 nM against WT and average IC₅₀ of 28.8 nM (range 1.5–125 nM) against mutant viruses with an average FC of 6.1 (range 0.3–26.6). Unsubstituted indoline and oxindole analogues were less active. The unsubstituted enamine analogue or analogues with small substituents were potent in the enzyme assay but tended to have modest, but similar activity across the MDR panel in the antiviral assays. Analogues with polar substituents (benzimidazole, pyridyl, hydroxy and amino) generally retained good potency against the enzyme but had poor antiviral activity. Analysis of the crystallographic structure revealed a hydrogen bonding pattern that suggests that a tautomer of the enamino-oxindole may explain the high intrinsic binding potency of this class of compounds.

CONCLUSIONS: HIV PIs containing enamino-oxindole substituents in P2′ are highly active against WT and MDR HIV isolates.

2008-06-10
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