Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists.

Autor: Emert-Sedlak LA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of School of Medicine, Pittsburgh, PA 15219 USA., Loughran HM; Fox Chase Chemical Diversity Center, Inc., Doylestown, PA 18902 USA., Shi H; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of School of Medicine, Pittsburgh, PA 15219 USA., Kulp JL 3rd; Conifer Point Pharmaceuticals, Doylestown, PA 18902 USA., Shu ST; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of School of Medicine, Pittsburgh, PA 15219 USA., Zhao J; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261 USA.; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15260 USA., Day BW; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261 USA.; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15260 USA.; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 USA., Wrobel JE; Fox Chase Chemical Diversity Center, Inc., Doylestown, PA 18902 USA., Reitz AB; Fox Chase Chemical Diversity Center, Inc., Doylestown, PA 18902 USA., Smithgall TE; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of School of Medicine, Pittsburgh, PA 15219 USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Mar 01; Vol. 26 (5), pp. 1480-1484. Date of Electronic Publication: 2016 Jan 21.
DOI: 10.1016/j.bmcl.2016.01.043
Abstrakt: The HIV-1 Nef accessory factor enhances viral replication and promotes immune system evasion of HIV-infected cells, making it an attractive target for drug discovery. Recently we described a novel class of diphenylpyrazolodiazene compounds that bind directly to Nef in vitro and inhibit Nef-dependent HIV-1 infectivity and replication in cell culture. However, these first-generation Nef antagonists have several structural liabilities, including an azo linkage that led to poor oral bioavailability. The azo group was therefore replaced with either a one- or two-carbon linker. The resulting set of non-azo analogs retained nanomolar binding affinity for Nef by surface plasmon resonance, while inhibiting HIV-1 replication with micromolar potency in cell-based assays without cytotoxicity. Computational docking studies show that these non-azo analogs occupy the same predicted binding site within the HIV-1 Nef dimer interface as the original azo compound. Computational methods also identified a hot spot for inhibitor binding within this site that is defined by conserved HIV-1 Nef residues Asp108, Leu112, and Pro122. Pharmacokinetic evaluation of the non-azo B9 analogs in mice showed that replacement of the azo linkage dramatically enhanced oral bioavailability without substantially affecting plasma half-life or clearance. The improved oral bioavailability of non-azo diphenylpyrazolo Nef antagonists provides a starting point for further drug lead optimization in support of future efficacy testing in animal models of HIV/AIDS.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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