RESUMO
A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.
Assuntos
Benzamidas/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Crystallographic structural information was used in the design and synthesis of a number of bioisosteric derivatives to replace the amide moiety in a lead series of p38α inhibitors which showed general hydrolytic instability in human liver preparations. Triazole derivative 13 was found to have moderate bioavailability in the rat and demonstrated potent in-vivo activity in an acute model of inflammation.
Assuntos
Amidas/química , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Ligação de Hidrogênio , Indóis/química , Indóis/farmacocinética , Inibidores de Proteínas Quinases/química , RatosRESUMO
The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.