RESUMO
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Assuntos
Benzimidazóis/química , Química Farmacêutica/métodos , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Benzimidazóis/síntese química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
Assuntos
Acetatos/síntese química , Integrina alfa4beta1/antagonistas & inibidores , Piperazinas/síntese química , Piperidinas/síntese química , Prolina/análogos & derivados , Acetatos/farmacocinética , Acetatos/farmacologia , Animais , Cães , Espectroscopia de Ressonância Magnética , Masculino , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Prolina/síntese química , Prolina/farmacocinética , Prolina/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.
