RESUMEN
A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.
Asunto(s)
Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Semivida , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Desnudos , Mutación , Neoplasias/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.
RESUMEN
A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Quinolinas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Glucemia/metabolismo , Línea Celular , Perros , Femenino , Humanos , Imidazoles/química , Insulina/sangre , Ligandos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Ratas , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).
Asunto(s)
Aldehídos/química , Benzaldehídos/química , Quinolinas/síntesis química , Hierro/química , Cetonas/química , Estructura Molecular , Oxidación-Reducción , Quinolinas/químicaRESUMEN
Until recently, the characterization of adenosine A(2B) receptors has been hampered by the lack of high affinity radioligands. This study describes the synthesis and in vitro characterization of the radiolabeled derivative of OSIP339391, a novel, potent, and selective pyrrolopyrimidine A(2B) antagonist. OSIP339391 had a selectivity of greater than 70-fold for A(2B) receptors over other human adenosine receptor subtypes. The radiolabel was introduced by hydrogenation of the acetylenic precursor with tritium gas resulting in the incorporation (on average) of three tritium atoms in the molecule, yielding a ligand with specific activity of 87Ci/mmol (3.2TBq/mmol). Using membranes from HEK-293 cells expressing the human recombinant A(2B) receptor, [3H]OSIP339391 was characterized in kinetic, saturation, and competition binding experiments. From the association and dissociation rate studies, the affinity was 0.41nM and in close agreement with that found in saturation binding experiments (0.17nM). In competition, binding studies using 0.5nM [3H]OSIP339391, the affinity of a range of agonists and antagonists was consistent with previously reported data. Thus, [3H]OSIP339391 is a novel, selective, and high affinity radioligand that can be a useful tool in the further exploration and characterization of recombinant and endogenous adenosine A(2B) receptors.