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

Content Provider	Scilit
Author	Emert-Sedlak, Lori A. Loughran, H. Marie Shi, Haibin Kulp, John L. Shu, Sherry T. Zhao, Jielu Day, Billy W. Wrobel, Jay E. Reitz, Allen B. Smithgall, Thomas E.
Copyright Year	2016
Description	Journal: Bioorganic & medicinal chemistry letters 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.
Related Links	http://europepmc.org/articles/pmc4756635?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756635/pdf
Ending Page	1484
Page Count	5
Starting Page	1480
ISSN	0960894X
DOI	10.1016/j.bmcl.2016.01.043
Journal	Bioorganic & medicinal chemistry letters
Issue Number	5
Volume Number	26
Language	English
Publisher	Elsevier BV
Publisher Date	2016-03-01
Access Restriction	Open
Subject Keyword	Journal: Bioorganic & medicinal chemistry letters Medicinal Chemistry Antiretroviral Drug Discovery
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Biochemistry Molecular Biology Clinical Biochemistry Molecular Medicine Pharmaceutical Science