Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies.
Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the -bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor . Inhibitor maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure.
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
Arun K
AK
Ghosh
Sandra
S
Gemma
Jun
J
Takayama
Abigail
A
Baldridge
Sofiya
S
Leshchenko-Yashchuk
Heather B
HB
Miller
Yuan-Fang
YF
Wang
Andrey Y
AY
Kovalevsky
Yashiro
Y
Koh
Irene T
IT
Weber
Hiroaki
H
Mitsuya
D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008024:Ligands; D014520:Urethane / Q000737:chemistry*
D001643:Bridged Bicyclo Compounds; D017320:HIV Protease Inhibitors; D008024:Ligands; D014520:Urethane; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1