RESUMEN
Aryl sulfonamide-based endothelin antagonists were synthesized and covalently linked to the reactive lysine of the m38C2 antibody to create a series of CovX-Bodies. These chemically programmed antibodies behaved as potent endothelin receptor antagonists in vitro and had antitumor efficacy in a prostate cancer xenograft model which, on a molar basis, far exceeded the activity of the parent small molecule.
Asunto(s)
Anticuerpos/química , Anticuerpos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Receptores de Endotelina/efectos de los fármacos , Animales , Células CHO , Cricetinae , Cricetulus , Antagonistas de los Receptores de la Endotelina A , Antagonistas de los Receptores de la Endotelina B , Humanos , Indicadores y Reactivos , Ratones , Ratones Desnudos , Conformación Molecular , Trasplante de Neoplasias , Relación Estructura-ActividadRESUMEN
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.
