RESUMEN
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.
Asunto(s)
Adenosina Monofosfato/metabolismo , Biomimética , Fructosa-Bifosfatasa/antagonistas & inhibidores , Organofosfonatos/química , Organofosfonatos/farmacología , Purinas/química , Administración Oral , Animales , Disponibilidad Biológica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Fructosa-Bifosfatasa/química , Fructosa-Bifosfatasa/metabolismo , Glucosa/metabolismo , Humanos , Concentración 50 Inhibidora , Hígado/enzimología , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Inhibidores de Caspasas , Hepatopatías/tratamiento farmacológico , Ácidos Pentanoicos/síntesis química , Adulto , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Disponibilidad Biológica , Caspasa 3 , Colestasis/tratamiento farmacológico , Colestasis/patología , Ensayos Clínicos Fase I como Asunto , Semivida , Hepatitis C Crónica/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Células Jurkat , Hígado/efectos de los fármacos , Hígado/patología , Hepatopatías/enzimología , Hepatopatías/etiología , Ratones , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Caspasas , Muerte Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Compuestos Heterocíclicos/farmacología , Cetonas/farmacología , Animales , Ácido Aspártico/química , Células Cultivadas , Compuestos Heterocíclicos/síntesis química , Cetonas/síntesis química , Ratones , Modelos Biológicos , Naftoles/química , Relación Estructura-Actividad , Valina/químicaRESUMEN
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.
Asunto(s)
Inhibidores de Caspasas , Dipéptidos/síntesis química , Dipéptidos/farmacología , Apoptosis/efectos de los fármacos , Carbamatos , Línea Celular , Humanos , Concentración 50 Inhibidora , Cinética , Enfermedades Neurodegenerativas/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
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.