RESUMEN
Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.
Asunto(s)
Amidas/farmacología , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Asunto(s)
Amidas/química , Complemento C1s/antagonistas & inhibidores , Diseño de Fármacos , Polietilenglicoles/química , Inhibidores de Proteasas/síntesis química , Tiofenos/química , Animales , Complemento C1s/metabolismo , Semivida , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.
Asunto(s)
Amidas/química , Antiinflamatorios/química , Receptores CCR2/antagonistas & inhibidores , Enfermedad Aguda , Administración Oral , Amidas/farmacología , Amidas/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Inflamación/tratamiento farmacológico , Ratones , Ratones Transgénicos , Ratas , Receptores CCR2/metabolismo , Relación Estructura-ActividadRESUMEN
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.
Asunto(s)
Amidas/farmacología , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Pegylated thrombopoietin mimetic peptide (PEG-TPOm) is a novel, potent thrombopoietin receptor agonist with low immunotoxicity potential that protects against chemotherapy-induced thrombocytopenia in preclinical animal models. The aim of this study was to develop a population pharmacokinetic and pharmacodynamic model of PEG-TPOm following single intravenous doses in healthy subjects. Data were obtained from a double-blind, randomized, placebo-controlled study. A model based on target-mediated drug disposition and precursor pool life spans was applied. Model evaluation was performed through predictive checks and bootstrap analysis. The half-life of PEG-TPOm ranged between 18 and 36 hours, and the estimated distributional volume was 5 L. The increase in platelet counts was observed after a 4-day delay, consistent with the megakaryocyte cell life span. The platelet life span was estimated to be 5 days. After maximum platelets counts were achieved on day 9, platelets returned back to baseline on day 29. Model-based simulations were undertaken to explore pharmacodynamic effects after multiple dosing. Weekly dosing produced a sustained pharmacodynamic response, whereas an interdosing interval >or=2 weeks resulted in fluctuating pharmacodynamic profiles. Thus, the mechanistic pharmacokinetic/pharmacodynamic model was suitable for describing the complex PEG-TPOm pharmacokinetics/pharmacodynamics, including target-mediated disposition, dose-dependent platelet stimulation, and mean life spans of thrombopoietic cell populations.
Asunto(s)
Modelos Biológicos , Polietilenglicoles/farmacología , Polietilenglicoles/farmacocinética , Receptores de Trombopoyetina/agonistas , Trombopoyetina/farmacología , Trombopoyetina/farmacocinética , Adulto , Simulación por Computador , Método Doble Ciego , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Recuento de Plaquetas , Polietilenglicoles/efectos adversos , Trombopoyetina/efectos adversos , Factores de TiempoRESUMEN
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Asunto(s)
Complemento C1s/antagonistas & inhibidores , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Animales , Sitios de Unión , Semivida , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Colágeno , Relación Dosis-Respuesta a Droga , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Factores de TiempoRESUMEN
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.
Asunto(s)
Antiinflamatorios/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Fenilendiaminas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Simulación por Computador , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Fenilendiaminas/síntesis química , Fenilendiaminas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC(50)s of 14 and 0.7 micromol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage-independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21(waf1/cip1) levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors.
Asunto(s)
Benzodiazepinonas/farmacología , Doxorrubicina/farmacología , Proteínas Proto-Oncogénicas c-mdm2/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Benzodiazepinas/química , Benzodiazepinas/farmacología , Benzodiazepinonas/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Ratones , Ratones Desnudos , Complejos Multiproteicos , Mutación , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
Asunto(s)
Benzodiazepinas/síntesis química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/agonistas , Benzodiazepinas/química , Benzodiazepinas/farmacología , Sitios de Unión , Línea Celular Tumoral , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Imitación Molecular , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2 , Estereoisomerismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
Development of alphavbeta3-integrin inhibitors has been hampered by a lack of pharmacodynamic endpoints to identify doses that inhibit alphavbeta3 in vivo. To address this need, we developed an alphavbeta3 radioreceptor assay (RRA) that could be performed in 100% plasma. The RRA was based on 125I-echistatin binding to plate-immobilized alphavbeta3. Small molecule alphavbeta3 inhibitors efficiently competed echistatin binding to alphavbeta3 when the assay was carried out in buffer. However, when carried out in 100% plasma, the RRA revealed a 45 to >3000-fold loss in compound potencies. The losses in potency reflected, in part, the high plasma protein binding by the compounds examined. The RRA was adapted as an ex vivo pharmacodynamic model. Echistatin binding was measured in the presence of plasma harvested at timed intervals from rats dosed with select compounds. Using this pharmacodynamic model, compound and dose selection was optimized for further testing in models of corneal angiogenesis. Moderate anti-angiogenic activity was achieved when rats were dosed sufficient to achieve sustained (>50%) plasma inhibition through the trough interval. Thus, the RRA provided a simple technique to rank order compound potency in plasma, and could find general use as an ex vivo pharmacodynamic assay to select compounds and doses for preclinical and clinical proof-of-principle studies.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Integrina alfaVbeta3/sangre , Ensayo de Unión Radioligante/métodos , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Proteínas Sanguíneas/metabolismo , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Masculino , Neovascularización Patológica/prevención & control , Péptidos/sangre , Péptidos/farmacocinética , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Imidazoles/síntesis química , Piperidinas/síntesis química , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/etiología , Artritis Experimental/patología , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Conformación Proteica , Ratas , Ratas Endogámicas Lew , Receptor de Factor Estimulante de Colonias de Macrófagos/química , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Imidazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Neoplasias Óseas/enzimología , Neoplasias Óseas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Ratas , Ratas Sprague-Dawley , Receptor de Factor Estimulante de Colonias de Macrófagos/sangre , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Especificidad por Sustrato , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.