A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor
antagonists were designed, which were elaborated either
by condensation of a lithiumsalt of 3-(N,N-dibenzyl)aminopropionic
acid methyl ester with ethyl benzoformate or by BaylisC
Hillman reaction of ethyl acrylate with ethyl benzoformate and
subsequent 1,4-addition of benzylamine, in the key steps. These
compounds bearing 4-(N,N-disubstituted)amino piperidine units
showed low nanomolar potency against the CCR5 receptor,
whereas molecules with a 4-phenylpiperidine moiety displayed
poor activity. Asymmetric synthesis of the most potent compound
23a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer
31, which showed IC50 values of 2.9 and 385.9 nm,respectively.
These results indicated that (3R,4S)-configuration in the
series of compounds is favored for their interaction with the
CCR5 receptor. The possible binding mode of these antagonists
with the CCR5 receptor was discussed using a computer-modeling
method. Compound 30 displayed excellent replication inhibition
of seven genetically diverse R5 HIV-1 strains in the PBMC
model, in a concentration-dependent manner with EC50 values
ranging from0.3 nm to 30 nm. This molecule showed oral bioavailabilities
of 41.2% and 21.6% in rats and dogs, respectively.
Thus, compound 30 is a promising candidate for the treatment
of HIV-1 infection.