Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors: heterocyclic ring systems containing P1' and P2' 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 C2 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 (EC50 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.
Kitchin
J
J
Department of Medicinal Chemistry, Glaxo Research and Development Limited, Greenford, Middlesex, United Kingdom.
Bethell
R C
RC
Cammack
N
N
Dolan
S
S
Evans
D N
DN
Holman
S
S
Holmes
D S
DS
McMeekin
P
P
Mo
C L
CL
Nieland
N
N
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004285:Dogs; D015726:Giant Cells / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D008969:Molecular Sequence Data; D010406:Penicillins / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010406:Penicillins