RESUMO
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.
Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , RatosRESUMO
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.