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Titolo:
SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF PENICILLIN-DERIVED HIV PROTEINASE-INHIBITORS - HETEROCYCLIC RING-SYSTEMS CONTAINING P-1' AND P-2' SUBSTITUENTS
Autore:
KITCHIN J; BETHELL RC; CAMMACK N; DOLAN S; EVANS DN; HOLMAN S; HOLMES DS; MCMEEKIN P; MO CL; NIELAND N; ORR DC; SAUNDERS J; SHENOY BEV; STARKEY ID; STORER R;
Indirizzi:
GLAXO RES & DEV LTD,DEPT MED CHEM GREENFORD UB6 0HE MIDDX ENGLAND GLAXO RES & DEV LTD,DEPT BIOMOLEC STRUCT GREENFORD UB6 0HE MIDDX ENGLAND GLAXO RES & DEV LTD,DEPT VIROL GREENFORD UB6 0HE MIDDX ENGLAND GLAXO RES & DEV LTD,DEPT DRUG METAB GREENFORD UB6 0HE MIDDX ENGLAND
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 22, volume: 37, anno: 1994,
pagine: 3707 - 3716
SICI:
0022-2623(1994)37:22<3707:SASOAS>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE; ISOSTERE; ANALOGS; POTENT; AGENT; AIDS; SITE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
J. Kitchin et al., "SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF PENICILLIN-DERIVED HIV PROTEINASE-INHIBITORS - HETEROCYCLIC RING-SYSTEMS CONTAINING P-1' AND P-2' SUBSTITUENTS", Journal of medicinal chemistry, 37(22), 1994, pp. 3707-3716

Abstract

As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinolinegrouping, also present in Ro 31-8959, is an effective replacement forone of the thiazolidine units in C-2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha,4a alpha,8a ro-N-(1,1-dimethylethyl)-3-isoquinolinecarboxamide gave diasteroisomers 34aand 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b withthiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in, vitro (EC(50) C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 12:55:59