RESUMO
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.
Assuntos
Biotina/química , Cisteína/química , Proteínas Metiltransferases/metabolismo , Cisteína/síntese química , Ensaios de Triagem em Larga Escala , Cinética , Proteínas Metiltransferases/química , Técnicas de Síntese em Fase Sólida , Especificidade por Substrato , Compostos de Tritil/químicaRESUMO
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.
Assuntos
Benzoxazóis/farmacocinética , Indóis/farmacocinética , Transtornos da Memória/tratamento farmacológico , Agonistas Muscarínicos/farmacocinética , Nootrópicos/farmacocinética , Receptor Muscarínico M1/metabolismo , Animais , Benzoxazóis/química , Benzoxazóis/uso terapêutico , Encéfalo/metabolismo , Indóis/química , Indóis/uso terapêutico , Agonistas Muscarínicos/química , Agonistas Muscarínicos/uso terapêutico , Nootrópicos/química , Nootrópicos/uso terapêutico , Oxindóis , RatosRESUMO
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.
Assuntos
Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Células CHO , Quimiotaxia de Leucócito/efeitos dos fármacos , Simulação por Computador , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Indicadores e Reagentes , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Receptores CCR8 , Relação Estrutura-Atividade , Células Th2/efeitos dos fármacosRESUMO
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.
