RESUMO
The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Imidazóis/farmacologia , Rim/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirrolidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sistema Cardiovascular/metabolismo , Humanos , Imidazóis/química , Rim/metabolismo , Testes de Função Renal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.