RESUMO
Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.
Assuntos
Cardiotônicos/síntese química , Cardiotônicos/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Disponibilidade Biológica , Cardiotônicos/farmacocinética , Biologia Computacional , Desenho de Fármacos , Receptores ErbB/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Modelos Moleculares , Conformação Molecular , Proteínas Serina-Treonina Quinases , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.