RESUMO
Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.
Assuntos
Benzimidazóis/química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Trifosfato de Adenosina/química , Administração Oral , Sítios de Ligação , Complexo CD3/química , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/química , Relação Estrutura-Atividade , Linfócitos T/metabolismoRESUMO
A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Aurora Quinases , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Poliploidia , Relação Estrutura-AtividadeRESUMO
The discovery, SAR, and X-ray crystal structure of novel biarylaminoacyl-(S)-2-cyano-pyrrolidines and biarylaminoacylthiazolidines as potent inhibitors of dipeptidyl peptidase IV (DPP IV) are reported.
Assuntos
Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Glicemia/metabolismo , Células CACO-2 , Dipeptidil Peptidase 4/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinética , Camundongos , Modelos Químicos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.