Emert-Sedlak, Lori A.; Loughran, H. Marie; Shi, Haibin; Kulp, John L. III; Shu, Sherry T.; Zhao, Jielu; Day, Billy W.; Wrobel, Jay E.; Reitz, Allen B.; Smithgall, Thomas E. published the artcile< Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists>, SDS of cas: 16799-05-6, the main research area is antiviral HIV AIDS Nef antagonist; Antiretroviral drug discovery; HIV Nef; HIV-1; Nef inhibitors.
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 the authors 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 nonazo 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 nonazo 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 nonazo 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 nonazo diphenylpyrazolo Nef antagonists provides a starting point for further drug lead optimization in support of future efficacy testing in animal models of HIV/AIDS.
Bioorganic & Medicinal Chemistry Letters published new progress about AIDS (disease). 16799-05-6 belongs to class chlorides-buliding-blocks, and the molecular formula is C8H8BrCl, SDS of cas: 16799-05-6.
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