RESUMO
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Assuntos
Benzopiranos/química , Inibidores Enzimáticos/química , Esterases/antagonistas & inibidores , Animais , Benzopiranos/farmacocinética , Benzopiranos/uso terapêutico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Esterases/metabolismo , Fêmur/fisiologia , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Assuntos
Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos Dessaturases/antagonistas & inibidores , Síndrome Metabólica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Dessaturase de Ácido Graxo Delta-5 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácidos Graxos Dessaturases/metabolismo , Humanos , Fígado/enzimologia , Síndrome Metabólica/enzimologia , Síndrome Metabólica/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The incidence of cognitive disorders such as Alzheimer's disease continues to increase unabated. While cures for such diseases have eluded investigators, progress is being made on alleviating certain symptoms of these diseases. Mouse knockouts of the proline transporter (PROT), a high affinity Na(+)/Cl(-)-dependent transporter, indicated its potential as a novel therapeutic target for cognition improvement. Herein we report our investigation into a novel class of PROT inhibitors.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Transtornos Cognitivos/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.