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 ( and ) and improved (, , and ) activities. Two potent water-soluble RN-18 analogues, and are also disclosed, and we describe the results of pharmacological studies with compound 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.