RESUMEN
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.
RESUMEN
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.
Asunto(s)
Receptores de Neuropéptido/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Humanos , Radioisótopos de Yodo/química , Unión Proteica , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacología , Ratas , Receptores de Neuropéptido/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/efectos de los fármacos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/química , Inhibidores de Integrasa VIH/química , Estructura Molecular , Naftiridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacocinética , Naftiridinas/síntesis química , Administración Oral , Animales , Células Cultivadas , Integrasa de VIH/efectos de los fármacos , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/farmacología , Humanos , Concentración 50 Inhibidora , Mutación , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.