RESUMEN
Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 °C as a solid, in solution, or on the resin.
Asunto(s)
Biotina/química , Cisteína/química , Proteína Metiltransferasas/metabolismo , Cisteína/síntesis química , Ensayos Analíticos de Alto Rendimiento , Cinética , Proteína Metiltransferasas/química , Técnicas de Síntesis en Fase Sólida , Especificidad por Sustrato , Compuestos de Tritilo/químicaRESUMEN
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Asunto(s)
Benzoxazoles/farmacocinética , Indoles/farmacocinética , Trastornos de la Memoria/tratamiento farmacológico , Agonistas Muscarínicos/farmacocinética , Nootrópicos/farmacocinética , Receptor Muscarínico M1/metabolismo , Animales , Benzoxazoles/química , Benzoxazoles/uso terapéutico , Encéfalo/metabolismo , Indoles/química , Indoles/uso terapéutico , Agonistas Muscarínicos/química , Agonistas Muscarínicos/uso terapéutico , Nootrópicos/química , Nootrópicos/uso terapéutico , Oxindoles , RatasRESUMEN
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
Asunto(s)
Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Células CHO , Quimiotaxis de Leucocito/efectos de los fármacos , Simulación por Computador , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Indicadores y Reactivos , Proteína Quinasa de Distrofia Miotónica , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Receptores CCR8 , Relación Estructura-Actividad , Células Th2/efectos de los fármacosRESUMEN
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.