RESUMO
p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed >or=20% inhibition of p38 at 10 microM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC(50) of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Ligantes , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química , Tiadiazóis/metabolismo , Tiadiazóis/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/químicaAssuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/química , Receptores do Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
The crystal structure of the title compound, C(16)H(11)FN(4)OS, was synthesized in the course of our studies on 1,2,4-triazolo[3,4-b][1,3,4]thia-diazo-les as inhibitors of p38 mitogen-activated protein kinase (MAPK). The three-dimensional data obtained were used to generate a three-dimensional pharmacophore model for in silico database screening. The dihedral angles between the central heterocylic system and the fluoro-phenyl and phenyl rings are 20.21â (3) and 5.43â (1)°, respectively; the dihedral angle between the two benzene rings is 15.80â (4)°.
