SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF PENICILLIN-DERIVED HIV PROTEINASE-INHIBITORS - HETEROCYCLIC RING-SYSTEMS CONTAINING P-1' AND P-2' SUBSTITUENTS

Citation
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
Citations number
27
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
37
Issue
22
Year of publication
1994
Pages
3707 - 3716
Database
ISI
SICI code
0022-2623(1994)37:22<3707:SASOAS>2.0.ZU;2-J
Abstract
As an extension of our earlier work based upon a single penicillin-der ived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C-2 symmetric penicillin-derived dime rs. Reaction of racemic epoxide 6 with [3S-[3 alpha,4a alpha,8a ro-N-( 1,1-dimethylethyl)-3-isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was deter mined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity ag ainst HIV-1 in, vitro (EC(50) C8166 cells = 50 nM). However, a poor ph armacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three sp ecies, precluded their development as potential antivirals.