RESUMO
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.
Assuntos
Amidas/química , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Pirazinas/química , Células 3T3 , Amidas/metabolismo , Amidas/farmacologia , Amidas/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Solubilidade , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.
