Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic.
A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.
Wu
Xiongyu
X
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Ohrngren
Per
P
Ekegren
Jenny K
JK
Unge
Johan
J
Unge
Torsten
T
Wallberg
Hans
H
Samuelsson
Bertil
B
Hallberg
Anders
A
Larhed
Mats
M
D000438:Alcohols / Q000737:chemistry*; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
C528860:(1-(N'-(4-hydroxy-4-(2-hydroxyindan-1-ylcarbamoyl)-5-phenylpentyl)-N'-(4-pyridin-4-ylbenzyl)hydrazinocarbonyl)-2,2-dimethylpropyl)carbamic acid methyl ester; D000438:Alcohols; D002219:Carbamates; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D007093:Imidazoles; D010069:Oxadiazoles; D011725:Pyridines