RESUMO
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene, loss of function variants of which cause an autosomal recessive lysosomal storage disorder, Gaucher disease (GD). Heterozygous variants of GBA1 are also known as the strongest common genetic risk factor for Parkinson's disease (PD). Restoration of GCase enzymatic function using a pharmacological chaperone strategy is considered a promising therapeutic approach for PD and GD. We identified compound 4 as a GCase pharmacological chaperone with sub-micromolar activity from a high-throughput screening (HTS) campaign. Compound 4 was further optimised to ER-001230194 (compound 25). ER-001230194 shows improved ADME and physicochemical properties and therefore represents a novel pharmacological chaperone with which to investigate GCase pharmacology further.
Assuntos
Doença de Gaucher , Doença de Parkinson , Humanos , Glucosilceramidase/genética , Mutação , Doença de Parkinson/tratamento farmacológico , Doença de Gaucher/tratamento farmacológico , LisossomosRESUMO
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.
Assuntos
Anti-Inflamatórios/farmacologia , Calreticulina/imunologia , Colite Ulcerativa/imunologia , Cicloexanos/farmacologia , Cadeias alfa de Integrinas/imunologia , Piperazinas/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Calreticulina/antagonistas & inibidores , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/citologia , Colo/imunologia , Colo/patologia , Cicloexanos/uso terapêutico , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Humanos , Cadeias alfa de Integrinas/metabolismo , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Piperazinas/uso terapêutico , Ligação Proteica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The potent in vitro lead compound, ER-803064 (2), a MEK1 and MEKK1 inhibitor inspired from natural product LL-Z1640-2 (f152A1), was further optimized to improve in vitro and in vivo potency. The modifications on C14 position led to discovery of the lead compounds 28 and 29, which regained full in vitro potency of f152A1 and showed higher in vivo potency by iv administration.
