RESUMO
Inhibition of FBPase is considered a promising way to reduce hepatic gluconeogenesis and therefore could be a potential approach to treat type 2 diabetes. Herein we report the discovery of a series of purine phosphonic acids as AMP mimics targeting the AMP site of FBPase, which was achieved using a structure-guided drug design approach. These non-nucleotide purine analogues inhibit FBPase in a similar manner and with similar potency as AMP. More importantly, several purine analogues exhibited potent cellular and in vivo glucose-lowering activities, thus achieving proof-of-concept for inhibiting FBPase as a drug discovery target. For example, compounds 4.11 and 4.13 are as equipotent as AMP with regard to FBPase inhibition. Furthermore, compound 4.11 inhibited glucose production in primary rat hepatocytes and significantly lowered blood glucose levels in fasted rats.
Assuntos
Monofosfato de Adenosina/metabolismo , Biomimética , Frutose-Bifosfatase/antagonistas & inibidores , Organofosfonatos/química , Organofosfonatos/farmacologia , Purinas/química , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Frutose-Bifosfatase/química , Frutose-Bifosfatase/metabolismo , Glucose/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/enzimologia , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
Assuntos
Inibidores de Caspase , Hepatopatias/tratamento farmacológico , Ácidos Pentanoicos/síntese química , Adulto , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Disponibilidade Biológica , Caspase 3 , Colestase/tratamento farmacológico , Colestase/patologia , Ensaios Clínicos Fase I como Assunto , Meia-Vida , Hepatite C Crônica/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Células Jurkat , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/etiologia , Camundongos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.
Assuntos
Inibidores de Caspase , Morte Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Compostos Heterocíclicos/farmacologia , Cetonas/farmacologia , Animais , Ácido Aspártico/química , Células Cultivadas , Compostos Heterocíclicos/síntese química , Cetonas/síntese química , Camundongos , Modelos Biológicos , Naftóis/química , Relação Estrutura-Atividade , Valina/químicaRESUMO
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
Assuntos
Inibidores de Caspase , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Apoptose/efeitos dos fármacos , Carbamatos , Linhagem Celular , Humanos , Concentração Inibidora 50 , Cinética , Doenças Neurodegenerativas/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.