Stereoisomers of cyclic urea HIV-1 protease inhibitors: synthesis and binding affinities.
We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino acid starting materials was used to prepare three isomers. Three additional isomers were prepared by synthetic routes utilizing L-tartaric acid and D-sorbitol as chiral starting materials. A stereoselective hydroxyl inversion of the cyclic urea trans-diol was used to prepare three additional isomers. In all 9 of the 10 possible cyclic urea stereoisomers were prepared, and their binding affinities are described.
Kaltenbach
R F
RF
DuPont Merck Pharmaceutical Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
Nugiel
D A
DA
Lam
P Y
PY
Klabe
R M
RM
Seitz
S P
SP
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D014508:Urea; D016333:HIV Protease