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

As an extension of our earlier work based upon a single penicillin-derived 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 dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha,4a alpha,8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3-isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined 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 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.