RESUMO
The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
Assuntos
Fibrose Pulmonar Idiopática/patologia , Integrina alfaV/química , Fenilbutiratos/química , Administração Oral , Animais , Antígenos de Neoplasias/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Integrina alfaV/metabolismo , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Fenilbutiratos/farmacocinética , Fenilbutiratos/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/química , Sítios de Ligação , Cristalografia por Raios X , Cinética , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Pirazóis/química , Piridinas/síntese química , Piridinas/metabolismo , Relação Estrutura-Atividade , Sulfonas/químicaRESUMO
An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Isoquinolinas/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Ftalimidas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Modelos Moleculares , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Relação Estrutura-AtividadeRESUMO
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.