RESUMO
A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model.
Assuntos
Antineoplásicos/farmacologia , Proteína Quinase CDC2/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase A , Aurora Quinases , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Neoplasias do Colo/patologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/síntese química , Benzazepinas/síntese química , Obesidade/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Aumento de Peso/efeitos dos fármacosRESUMO
[Chemical reaction: see text] The first synthesis of the C1-C13 fragment of 2,3-dihydrodorrigocin A has been achieved from 6-bromohexanoic acid in 14 linear steps and an overall yield of 2%. The configurations of the stereogenic centers C8, C9, and C10 have been determined to be the same as for migrastatin.
Assuntos
Hidroxilação , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Piperidonas/síntese química , EstereoisomerismoRESUMO
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.