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