RESUMEN
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
Asunto(s)
Ácidos/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Pirroles/químicaRESUMEN
Exploration of the SAR around a series of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines led to the discovery of novel pyrrolopyridine inhibitors of the IGF-1R tyrosine kinase. Several compounds demonstrated nanomolar potency in enzyme and cellular mechanistic assays.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Piridinas/química , Pirroles/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptor IGF Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Descubrimiento de Drogas , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/química , RatasRESUMEN
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Asunto(s)
MAP Quinasa Quinasa 4/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Modelos Moleculares , Pirimidinas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Asunto(s)
Antineoplásicos/química , Receptores ErbB/antagonistas & inhibidores , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Ratones , Farmacocinética , Pirimidinas/síntesis química , Pirrolidinas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Química Farmacéutica/métodos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tiofenos/química , Ciclo Celular , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Mitosis , Modelos Químicos , Conformación Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/química , Proteínas Proto-Oncogénicas/química , Solubilidad , Proteínas Supresoras de Tumor , Quinasa Tipo Polo 1RESUMEN
The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC(50) value of 0.2 microM. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-alpha production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.
Asunto(s)
Anisoles/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Anisoles/farmacología , Artritis Experimental/patología , Células Cultivadas , Humanos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Virus del Sarcoma Felino/efectos de los fármacos , Virus del Sarcoma Felino/enzimologíaRESUMEN
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1')-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1') constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.
Asunto(s)
Amidas/química , Química Orgánica/métodos , Pirimidinas/química , Pirroles/química , Carbono/química , Catálisis , Cloruros/química , Diseño de Fármacos , Modelos QuímicosRESUMEN
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Piridinas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Área Bajo la Curva , Perros , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Leucocitos Mononucleares/efectos de los fármacos , Sistema de Señalización de MAP Quinasas , Piridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Piridinas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Cristalografía por Rayos X , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa de Linfoma Anaplásico , Animales , Glucemia/metabolismo , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Ratones , Fosforilación/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A novel series of potent substituted anilinoquinolines were discovered as c-fms inhibitors. The potency could be manipulated upon modification of the C4 aniline and C7 aryl functionality. Pharmacokinetic analysis identified a metabolically stable analog suitable for further investigative work.
Asunto(s)
Compuestos de Anilina/química , Quinolinas/síntesis química , Quinolinas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Concentración 50 Inhibidora , Modelos Animales , Modelos Moleculares , Estructura Molecular , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 microM and was inactive against 26 other kinases. GW2580 at 1 microM completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.