Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier

By employing pharmacophore-based design and the privileged fragments reassembly, a series of piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an efficient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure. Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel scaffolds for further development of potent CCR5 inhibitors.

Graphical abstractBased on the putative 3-domain pharmacophore model for CCR5 inhibition, piperidine-/tropane-/piperazine-bridged 1-acyl-1,3-propanediamine compounds were designed and synthesized, focused on the basic center carrier structure. Thus 4-methyl-4-aminopiperidine containing analogs were identified as new scaffold CCR5 antagonists with nanomolar IC50 values.Figure optionsDownload full-size imageDownload as PowerPoint slide