RESUMO
Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC(50) values down to 25nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.
Assuntos
Amidas/uso terapêutico , Calpaína/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/uso terapêutico , Dipeptídeos/química , Distrofia Muscular Animal/tratamento farmacológico , Amidas/química , Animais , Diafragma/efeitos dos fármacos , Diafragma/patologia , Camundongos , Camundongos Endogâmicos mdx , Estrutura Molecular , Distrofia Muscular Animal/enzimologiaRESUMO
In a continuation of our efforts to simplify the structure of our neurokinin antagonists, a series of substituted biphenyl derivatives has been prepared. Several compounds exhibit potent affinities for both the NK(1) receptor (<10nM) and for the NK(2) receptor (<50 nM). Details on the design, synthesis, biological activities, SAR and conformational analysis of this new class of dual NK(1)/NK(2) receptor antagonists are presented.
