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1.
Biol Pharm Bull ; 46(9): 1223-1230, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37661402

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.


Asunto(s)
Antineoplásicos , Artritis Reumatoide , Animales , Ratas , Metotrexato/farmacología , Metotrexato/uso terapéutico , Factor Estimulante de Colonias de Macrófagos , Calidad de Vida , Artritis Reumatoide/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras
2.
Biol Pharm Bull ; 43(12): 1884-1892, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33268706

RESUMEN

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Azetidinas/uso terapéutico , Densidad Ósea/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Azetidinas/farmacología , Densidad Ósea/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Osteoclastos/metabolismo , Osteoclastos/patología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patología
3.
Biol Pharm Bull ; 43(2): 325-333, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32009119

RESUMEN

Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.


Asunto(s)
Azetidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Azetidinas/farmacocinética , Células Cultivadas , Citocinas/sangre , Citocinas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Ratas Endogámicas Lew , Receptor trkA/metabolismo
4.
Rinsho Byori ; 64(4): 442-444, 2016 May.
Artículo en Japonés | MEDLINE | ID: mdl-29182815

RESUMEN

At the symposium entitled "challenging future of bio-bank business," the following topics were presented: 1) Bio-bank in the field of preemptive diagnosis by Prof. Saito (Fujita Health University), comprising personal health records of healthy individuals (3,000 as of Nov., 2015) consolidated with bio-resources under the or- ganization of the Resource Center for Health Science; 2) Cord blood banking by Mr. Asai (Stem Cell Institute Inc.), which was started in 1999, including mesenchymal stem cells for autologous purposes; 3) Bio-banking for regenerative medicine by Mr. Esaki (Healthcare Service Division of METI), in which stem cells from cord blood, surgical tissues, and dental pulp targeted for allogeneic purposes were emphasized; 4) Demonstration of a reference/search program for bio-bank business with a focus on medical information, a dietary question- naire (BDHQ), and stress questionnaires (GHQ-28 and CES-D) by Mr. Sakurai (SEIKOTEC Co., Ltd.). In iddition. Mr. Mivata (Nikkei BP. Inc.) helned facilitate the symposium.


Asunto(s)
Bancos de Muestras Biológicas , Sangre Fetal , Humanos , Medicina Regenerativa , Donantes de Tejidos
5.
Phys Chem Chem Phys ; 14(40): 14049-60, 2012 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-22983117

RESUMEN

The location, orientation, and dynamics of hydrophobic small molecules in lipid membranes are studied through combined use of solution-state (1)H-NMR and MD simulation. 1-Naphthol and 1-methylnaphthalene were adopted as the small molecules with or without hydrophilic groups. The nuclear Overhauser effect (NOE) measurement was performed for large unilamellar vesicles (100 nm in diameter) composed of dimyristoylphosphatidylcholine (DMPC) and the naphthalene derivative. The transient NOE-SE (spin-echo) scheme previously reported (J. Phys. Chem. B, 2011, 115, 9106-9115) was employed to quantitatively determine the NOE cross relaxation rate constant between DMPC and the naphthalene derivative. The observed NOE shows that both the naphthalene derivatives distribute over a wide domain across the normal of the essentially planar membrane ranging from the hydrophobic core to the hydrophilic headgroup. The experimental NOE information was further refined in combination with the analysis of time correlation functions in MD simulation. It was found that 1-naphthol exhibits a slight preference for pointing its OH group toward the hydrophilic domain of the membrane and that no definite preference can be concluded for the orientation of 1-methylnaphthalene. When 1-naphthol and 1-methylnaphthalene are compared, the NOE is stronger for 1-naphthol due to the restricted motion of the OH group. The slowdown of the 1-naphthol motion is also evidenced by the (1)H spectral line width.


Asunto(s)
Dimiristoilfosfatidilcolina/metabolismo , Lípidos de la Membrana/metabolismo , Simulación de Dinámica Molecular , Naftalenos/metabolismo , Naftoles/metabolismo , Liposomas Unilamelares/metabolismo , Dimiristoilfosfatidilcolina/química , Espectroscopía de Resonancia Magnética , Lípidos de la Membrana/química , Naftalenos/química , Naftoles/química , Liposomas Unilamelares/química
6.
Eur J Pharmacol ; 668(1-2): 331-6, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21810422

RESUMEN

Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 µg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.


Asunto(s)
Benzoatos/farmacología , Osteogénesis/efectos de los fármacos , Ovariectomía , Hormona Paratiroidea/metabolismo , Propanolaminas/farmacología , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Animales , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Células COS , Chlorocebus aethiops , Femenino , Humanos , Propanolaminas/administración & dosificación , Propanolaminas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Proteínas Recombinantes/farmacología
7.
ACS Med Chem Lett ; 2(3): 238-42, 2011 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-24900301

RESUMEN

Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.

8.
Bioorg Med Chem Lett ; 20(12): 3809-13, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20472433

RESUMEN

Synthesis and structure-activity relationship studies on a new aminopropandiol class of derivatives as calcium-sensing receptor antagonists are described. Modification of the phenolic moiety of a calcilytic compound NPS 2143 led to the identification of an orally available compound (R,R)-31 which demonstrated a rapid and transient stimulation of PTH release in rats.


Asunto(s)
Propanolaminas/química , Animales , Disponibilidad Biológica , Osteoporosis/tratamiento farmacológico , Hormona Paratiroidea/metabolismo , Propanolaminas/farmacología , Propanolaminas/uso terapéutico , Ratas , Receptores Sensibles al Calcio/antagonistas & inhibidores , Relación Estructura-Actividad
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