Discovery of Bioavailable 4,4-Disubstituted Piperidines as Potent Ligands of the Chemokine Receptor 5 and Inhibitors of the Human Immunodeficiency Virus-1

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1 beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC(50) = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC(50) = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.