RESUMEN
Although KRAS protein had been classified as an undruggable target, inhibitors of KRAS G12C mutant protein were recently reported to show clinical efficacy in solid tumors. In our previous report, we identified 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivative (1) as a KRAS G12C inhibitor that covalently binds to Cys12 of KRAS G12C protein. Compound 1 exhibited potent cellular pERK inhibition and cell growth inhibition against a KRAS G12C mutation-positive cell line and showed an antitumor effect on subcutaneous administration in an NCI-H1373 (KRAS G12C mutation-positive cell line) xenograft mouse model in a dose-dependent manner. In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.
Asunto(s)
Neoplasias Pulmonares , Neoplasias , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación , Relación Estructura-Actividad , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Humanos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Pirrolidinas/farmacocinéticaRESUMEN
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Administración Oral , Animales , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Humanos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Biología Computacional , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Carbamatos/farmacología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Administración Oral , Amina Oxidasa (conteniendo Cobre)/sangre , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Carbamatos/administración & dosificación , Carbamatos/química , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP2C19/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Glicina/análogos & derivados , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Espectroscopía de Protones por Resonancia Magnética , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1mg/kg.