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Synthesis and Biological Evaluation of 1,3,3,4‐Tetrasubstituted Pyrrolidine CCR5 Receptor Antagonists. Discovery of a Potent and Orally Bioavailable Anti‐HIV Agent
Author(s) -
Ma Dawei,
Yu Shanghai,
Li Ben,
Chen Li,
Chen Renhai,
Yu Kunqian,
Zhang Linqi,
Chen Zhiwei,
Zhong Dafang,
Gong Zheng,
Wang Renxiao,
Jiang Hualiang,
Pei Gang
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600182
Subject(s) - pyrrolidine , moiety , chemistry , ccr5 receptor antagonist , stereochemistry , piperidine , receptor , enantiomer , potency , benzylamine , chemokine receptor ccr5 , in vitro , biochemistry , chemokine receptor , chemokine , medicinal chemistry
A series of 1,3,3,4‐tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3‐( N,N ‐dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis–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 23 a gave rise to the (3 R ,4 S )‐enantiomer 30 and the (3 S ,4 R )‐enantiomer 31 , which showed IC 50 values of 2.9 and 385.9 n M , respectively. These results indicated that (3 R ,4 S )‐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 EC 50 values ranging from 0.3 n M to 30 n M . 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.