ABSTRACT
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats.
Subject(s)
Receptors, Neuropeptide/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Blood-Brain Barrier/metabolism , Central Nervous System/metabolism , Humans , Iodine Radioisotopes/chemistry , Protein Binding , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/pharmacology , Rats , Receptors, Neuropeptide/metabolism , Structure-Activity RelationshipABSTRACT
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/drug effects , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/chemistry , HIV Integrase Inhibitors/chemistry , Molecular Structure , Naphthyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.
ABSTRACT
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , Naphthyridines/chemical synthesis , Administration, Oral , Animals , Cells, Cultured , HIV Integrase/drug effects , HIV Integrase/genetics , HIV Integrase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mutation , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A concise total asymmetric synthesis of the tetrahydronaphthyridine alkaloid (-)-normalindine has been accomplished via the addition of a laterally metalated 4-methyl-3-cyanopyridine to a sulfinimine (N-sulfinyl imine) as the key step.