RESUMEN
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Asunto(s)
Aminoquinolinas/síntesis química , Aminoquinolinas/toxicidad , Compuestos de Anilina/síntesis química , Compuestos de Anilina/toxicidad , Sistema Cardiovascular/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Aminoquinolinas/química , Aminoquinolinas/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Cobayas , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Miocitos Cardíacos/efectos de los fármacos , RatasRESUMEN
Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.