Studies on the Structure-Activity Relationship of 1,3,3,4-Tetra-substituted Pyrrolidine Embodied CCR5 Receptor Antagonists. Part 2: Discovery of Highly Potent Anti-Hiv Agents.

Modification of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists revealed that introducing a fluoro group at the 3-position of the 3-phenyl group to reduce metabolism did not adversely affect the high potency against HIV infection, and that replacing the piperidine ring with a tropane ring could deliver the most potent anti-HIV agents. Stereochemistry of the substituted tropane ring is essential for maintaining the potent anti-HIV activity because only exo-isomers displayed subnanomolar whole cell activity.