RESUMO
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
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.
Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Benzotiazóis/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Camundongos , Modelos Moleculares , Proteínas Tirosina Quinases/química , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Desenho de Fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Oxidiazóis/síntese química , Oxidiazóis/uso terapêutico , Administração Oral , Animais , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/química , RatosRESUMO
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Assuntos
Antidepressivos Tricíclicos/síntese química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos Tricíclicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/química , Humanos , Ligação de Hidrogênio , Microssomos/efeitos dos fármacos , Modelos Químicos , Conformação Molecular , Isoformas de Proteínas , Ratos , Antagonistas da Serotonina/farmacologiaRESUMO
Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallography and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the molecular interactions. The fragment molecular orbital (FMO) quantum-mechanical (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodology was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high-throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range.