ABSTRACT
The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R(1) and R(2) ) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R(1) substituents and a small (bromo-) R(2) substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R(1) position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.
Subject(s)
HIV Protease Inhibitors/pharmacokinetics , Intestinal Mucosa/physiology , Caco-2 Cells , HIV-1 , Humans , PermeabilityABSTRACT
By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.
Subject(s)
Alcohols/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Alcohols/pharmacology , Antiviral Agents/pharmacology , Crystallography, X-Ray , HIV Protease/genetics , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/genetics , Inhibitory Concentration 50 , Molecular Mimicry , Mutation, MissenseABSTRACT
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.
Subject(s)
Alcohols/chemistry , Carbamates/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Hydrazines/chemical synthesis , Models, Molecular , Binding Sites , Carbamates/chemistry , Carbamates/pharmacology , Cell Line , Crystallography, X-Ray , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Humans , Hydrazines/chemistry , Hydrazines/pharmacology , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Mimicry , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , StereoisomerismABSTRACT
A short synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains has been developed.
Subject(s)
Alcohols/chemistry , HIV Protease Inhibitors/chemistry , HIV-1/enzymology , Crystallography, X-RayABSTRACT
Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
Subject(s)
Alcohols/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV Protease/chemistry , Indans/chemical synthesis , Alcohols/chemistry , Alcohols/pharmacology , Binding Sites , Catalysis , Cell Line , Crystallography, X-Ray , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , Humans , Hydrogen Bonding , Indans/chemistry , Indans/pharmacology , Microwaves , Molecular Mimicry , PalladiumABSTRACT
Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1'-P3' residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
Subject(s)
Alcohols/chemistry , HIV Protease Inhibitors/chemical synthesis , HIV Protease/chemistry , HIV Protease/metabolism , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Drug Resistance, Viral , HIV Protease/genetics , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/isolation & purification , Humans , Molecular Conformation , Molecular Mimicry , Mutation , StereoisomerismABSTRACT
New nitrogen- and sulfur-containing compounds, bicyclic and monocyclic, were prepared and evaluated as ligands in the transfer hydrogenation of acetophenone. Utilising [Ir(COD)Cl]2 as metal precursor the best result, 80% ee, was obtained using a bicyclic sulfoxide ligand.
