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Titolo:
SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF PENICILLIN-DERIVED HIV PROTEINASE-INHIBITORS CONTAINING A STEREOCHEMICALLY UNIQUE PEPTIDE ISOSTERE
Autore:
HOLMES DS; BETHELL RC; CAMMACK N; CLEMENS IR; KITCHIN J; MCMEEKIN P; MO CL; ORR DC; PATEL B; PATERNOSTER IL; STORER R;
Indirizzi:
GLAXO GRP RES LTD,DEPT MED CHEM 2 GREENFORD UB6 0HE MIDDX ENGLAND GLAXO GRP RES LTD,DEPT VIROL GREENFORD UB6 0HE MIDDX ENGLAND
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 21, volume: 36, anno: 1993,
pagine: 3129 - 3136
SICI:
0022-2623(1993)36:21<3129:SASOAS>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN IMMUNODEFICIENCY VIRUS; PROTEASE INHIBITOR; ANALOGS; PEPSTATIN; AIDS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
D.S. Holmes et al., "SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF PENICILLIN-DERIVED HIV PROTEINASE-INHIBITORS CONTAINING A STEREOCHEMICALLY UNIQUE PEPTIDE ISOSTERE", Journal of medicinal chemistry, 36(21), 1993, pp. 3129-3136

Abstract

A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety. Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50 = 0.15 muM). Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere. This wasa potent competitive inhibitor (K(i) = 0.25 nM) with antiviral activity against HIV-1 in vitro (5 muM). Neither modification to the benzyl group in an attempt to improve interaction with the S2' pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/07/20 alle ore 22:06:22