ABSTRACT
Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Infections/drug therapy , HIV-1/drug effects , Phenanthrolines/chemistry , Phenanthrolines/pharmacology , Receptors, CXCR4/antagonists & inhibitors , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line , Dogs , Humans , Models, Molecular , Phenanthrolines/chemical synthesis , Phenanthrolines/pharmacokinetics , Rats , Receptors, CXCR4/metabolismABSTRACT
Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.
Subject(s)
Antiviral Agents/therapeutic use , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Antiviral Agents/pharmacology , Cell Line, Tumor , HIV/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , Humans , Models, ChemicalABSTRACT
Synthesis of a series of tetrahydrocarbazole amides with potent activity against human papillomaviruses is described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole and the amide are outlined and resulting changes in antiviral activity and certain developability parameters are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the single digit nanomolar range were identified and N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide was selected for further evaluation.
Subject(s)
Amides/chemical synthesis , Carbazoles/chemical synthesis , Papillomaviridae/metabolism , Administration, Oral , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Carbazoles/pharmacology , Chlorocebus aethiops , Cytochrome P-450 Enzyme System/chemistry , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Vero CellsABSTRACT
The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.
