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Article: Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent

TitleSynthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent
Authors
Issue Date2007
PublisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/110485305
Citation
Chemmedchem, 2007, v. 2 n. 2, p. 187-193 How to Cite?
AbstractA 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 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 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. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
Persistent Identifierhttp://hdl.handle.net/10722/157505
ISSN
2015 Impact Factor: 2.98
2015 SCImago Journal Rankings: 1.183
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMa, Den_US
dc.contributor.authorYu, Sen_US
dc.contributor.authorLi, Ben_US
dc.contributor.authorChen, Len_US
dc.contributor.authorChen, Ren_US
dc.contributor.authorYu, Ken_US
dc.contributor.authorZhang, Len_US
dc.contributor.authorChen, Zen_US
dc.contributor.authorZhong, Den_US
dc.contributor.authorGong, Zen_US
dc.contributor.authorWang, Ren_US
dc.contributor.authorJiang, Hen_US
dc.contributor.authorPei, Gen_US
dc.date.accessioned2012-08-08T08:50:40Z-
dc.date.available2012-08-08T08:50:40Z-
dc.date.issued2007en_US
dc.identifier.citationChemmedchem, 2007, v. 2 n. 2, p. 187-193en_US
dc.identifier.issn1860-7179en_US
dc.identifier.urihttp://hdl.handle.net/10722/157505-
dc.description.abstractA 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 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 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. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.en_US
dc.languageengen_US
dc.publisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/110485305en_US
dc.relation.ispartofChemMedChemen_US
dc.subject.meshAdministration, Oralen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAnti-Hiv Agents - Administration & Dosage - Chemical Synthesis - Pharmacokineticsen_US
dc.subject.meshBiological Availabilityen_US
dc.subject.meshDogsen_US
dc.subject.meshHiv Infections - Metabolismen_US
dc.subject.meshModels, Chemicalen_US
dc.subject.meshPyrrolidines - Administration & Dosage - Chemical Synthesis - Pharmacokineticsen_US
dc.subject.meshRatsen_US
dc.subject.meshReceptors, Ccr5 - Antagonists & Inhibitorsen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.subject.meshVirus Replication - Drug Effects - Physiologyen_US
dc.titleSynthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agenten_US
dc.typeArticleen_US
dc.identifier.emailChen, Z:zchenai@hkucc.hku.hken_US
dc.identifier.authorityChen, Z=rp00243en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/cmdc.200600182en_US
dc.identifier.pmid17163560en_US
dc.identifier.scopuseid_2-s2.0-39449128909en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-39449128909&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume2en_US
dc.identifier.issue2en_US
dc.identifier.spage187en_US
dc.identifier.epage193en_US
dc.identifier.isiWOS:000202946700006-
dc.publisher.placeGermanyen_US
dc.identifier.scopusauthoridMa, D=7402075894en_US
dc.identifier.scopusauthoridYu, S=8668878400en_US
dc.identifier.scopusauthoridLi, B=15840303700en_US
dc.identifier.scopusauthoridChen, L=35788785000en_US
dc.identifier.scopusauthoridChen, R=24460491700en_US
dc.identifier.scopusauthoridYu, K=8750695900en_US
dc.identifier.scopusauthoridZhang, L=8783285300en_US
dc.identifier.scopusauthoridChen, Z=35271180800en_US
dc.identifier.scopusauthoridZhong, D=7102032555en_US
dc.identifier.scopusauthoridGong, Z=36985049800en_US
dc.identifier.scopusauthoridWang, R=7405340239en_US
dc.identifier.scopusauthoridJiang, H=7404466056en_US
dc.identifier.scopusauthoridPei, G=7101981020en_US

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