ABSTRACT
SAR studies on the para-fluorobenzyl moiety of tricyclic HIV integrase inhibitors are discussed and lead compounds with potency and PK properties comparable to raltegravir were identified.
Subject(s)
Fluorobenzenes/chemistry , HIV Integrase Inhibitors/chemical synthesis , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Binding, Competitive/physiology , Biological Availability , Cell Line , Dogs , Fluorobenzenes/metabolism , Fluorobenzenes/pharmacology , HIV Integrase Inhibitors/administration & dosage , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/metabolism , Humans , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the 'halobenzyl tail' at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC(50) and t(1/2) in animal PK studies.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Dogs , Drug Design , HIV Integrase Inhibitors/chemistry , Humans , Molecular Structure , Pyrroles/chemistry , Quinolines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A series of C5-aza tricyclic HIV integrase inhibitors was prepared. A highly potent and orally bioavailable compound (compound 9) was identified and selected for development.
Subject(s)
Azacitidine/analogs & derivatives , HIV Integrase Inhibitors/pharmacology , Administration, Oral , Animals , Azacitidine/chemistry , Azacitidine/pharmacology , Biological Availability , Crystallography, X-Ray , Dogs , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , Humans , Organic Chemicals/chemistry , Organic Chemicals/pharmacokinetics , Organic Chemicals/pharmacology , Pyrrolidinones , Raltegravir Potassium , RatsABSTRACT
Camptothecin-based drugs, because of their poor solubility and labile lactone ring, pose challenges for drug delivery. The purpose of this research was to develop a nanoparticle delivery system for camptotheca alkaloids. After initial investigations SN-38 was selected as the candidate camptotheca alkaloid for further development. Nanoparticles comprising SN-38, phospholipids and polyethylene glycol were developed and studied in vitro and in vivo. The SN-38 formulations were stable in human serum albumin and high lactone concentrations were observed even after 3 h. In vivo studies in nude mice showed prolonged half-life of the active (lactone form) drug in whole blood and increased efficacy compared to Camptosar in a mouse xenograft tumor model.
