SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor.

We describe structure-activity relationship and optimization studies of RN-18, an HIV-1 Vif-APOBEC3G axis inhibitor. Targeted modifications of RN-18 ring-C, ring-B, ring-A, bridge A-B, and bridge B-C were performed to identify the crucial structural features, which generated new inhibitors with similar (4g and 4i) and improved (5, 8b, and 11) activities. Two potent water-soluble RN-18 analogues, 17 and 19, are also disclosed, and we describe the results of pharmacological studies with compound 19. The findings described here will be useful in the development of more potent Vif inhibitors and in the design of probes to identify the target protein of RN-18 and its analogues.

[1]  J. Unge,et al.  Difluoromethylbenzoxazole pyrimidine thioether derivatives: a novel class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors. , 2011, Journal of medicinal chemistry.

[2]  Arun K. Ghosh,et al.  Design, synthesis, and X-ray structure of substituted bis-tetrahydrofuran (bis-THF)-derived potent HIV-1 protease inhibitors , 2011 .

[3]  Akbar Ali,et al.  Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones. , 2010, Journal of medicinal chemistry.

[4]  Celia A Schiffer,et al.  Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV. , 2010, Journal of chemical theory and computation.

[5]  G. P. V. van Klink,et al.  Ligand-free copper-catalyzed C-S coupling of aryl iodides and thiols. , 2008, The Journal of organic chemistry.

[6]  A. Takaori-Kondo,et al.  Cytidine deaminases as a weapon against retroviruses and a new target for antiviral therapy. , 2008, Mini reviews in medicinal chemistry.

[7]  Hong Cao,et al.  Small-molecule inhibition of HIV-1 Vif , 2008, Nature Biotechnology.

[8]  K. Nicolaou,et al.  A mild and selective method for the hydrolysis of esters with trimethyltin hydroxide. , 2005, Angewandte Chemie.

[9]  A. Shaabani,et al.  Green oxidations. The use of potassium permanganate supported on manganese dioxide , 2004 .

[10]  B. Strack,et al.  Vif Overcomes the Innate Antiviral Activity of APOBEC3G by Promoting Its Degradation in the Ubiquitin-Proteasome Pathway* , 2004, Journal of Biological Chemistry.

[11]  S. Buchwald,et al.  A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides and thiols. , 2002, Organic letters.

[12]  M. Malim,et al.  Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein , 2002, Nature.

[13]  Arthur J. Olson,et al.  Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants , 1999 .