title: Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.
abstract: 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 (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC(50) 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 EC(50) values ranging from 0.3 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.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China. madw@mail.sioc.ac.cn <madw@mail.sioc.ac.cn>
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
authors.forename: Shanghai
authors.initials: S
authors.lastname: Yu
authors.forename: Ben
authors.initials: B
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Renhai
authors.initials: R
authors.lastname: Chen
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.forename: Zheng
authors.initials: Z
authors.lastname: Gong
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D015658:HIV Infections / Q000378:metabolism; D008956:Models, Chemical; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D011759:Pyrrolidines