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Cathepsin k inhibitors

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https://www.readbyqxmd.com/read/28629344/antiresorptive-effect-of-a-cathepsin-k-inhibitor-ono-5334-and-its-relationship-to-bmd-increase-in-a-phase-ii-trial-for-postmenopausal-osteoporosis
#1
Makoto Tanaka, Yoshitaka Hashimoto, Chihiro Hasegawa, Steve Deacon, Richard Eastell
BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship...
June 19, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28623674/cathepsin-k-in-lymphangioleiomyomatosis-lam-cell-fibroblast-interactions-enhance-protease-activity-by-extracellular-acidification
#2
Arundhati Dongre, Debbie Clements, Andrew J Fisher, Simon R Johnson
Lymphangioleiomyomatosis (LAM) is a rare disease in which clonal LAM cells infiltrate the lungs and lymphatics. In association with recruited fibroblasts, LAM cells form nodules adjacent to lung cysts. It is hypothesized that LAM nodule-derived proteases lead to cyst formation. On protease gene-expression profiling in whole-lung tissue, cathepsin K was 40-fold overexpressed in LAM compared with control lungs (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein in LAM nodules but not in control lungs...
June 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28605601/a-new-sugarcane-cystatin-strongly-binds-to-dental-enamel-and-reduces-erosion
#3
A C Santiago, Z N Khan, M C Miguel, C C Gironda, A Soares-Costa, V T Pelá, A L Leite, J M Edwardson, M A R Buzalaf, F Henrique-Silva
Cystatin B was recently identified as an acid-resistant protein in acquired enamel pellicle; it could therefore be included in oral products to protect against caries and erosion. However, human recombinant cystatin is very expensive, and alternatives to its use are necessary. Phytocystatins are reversible inhibitors of cysteine peptidases that are found naturally in plants. In plants, they have several biological and physiological functions, such as the regulation of endogenous processes, defense against pathogens, and response to abiotic stress...
June 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28580393/estrogen-depletion-and-drug-treatment-alter-the-microstructure-of-type-i-collagen-in-bone
#4
Meagan A Cauble, Matthew J Muckley, Ming Fang, Jeffrey A Fessler, Kathleen Welch, Edward D Rothman, Bradford G Orr, Le T Duong, Mark M Banaszak Holl
The impact of estrogen depletion and drug treatment on type I collagen fibril nanomorphology and collagen fibril packing (microstructure) was evaluated by atomic force microscopy (AFM) using an ovariectomized (OVX) rabbit model of estrogen deficiency induced bone loss. Nine month-old New Zealand white female rabbits were treated as follows: sham-operated (Sham; n = 11), OVX + vehicle (OVX + Veh; n = 12), OVX + alendronate (ALN, 600 μg/kg/wk., s.c.; n = 12), and OVX + cathepsin-K inhibitor L-235 (CatKI, 10 mg/kg, daily, p...
December 2016: Bone Reports
https://www.readbyqxmd.com/read/28575856/trans-4-4-dihydroxystilbene-dhs-inhibits-human-neuroblastoma-tumor-growth-and-induces-mitochondrial-and-lysosomal-damages-in-neuroblastoma-cell-lines
#5
Bhaskar Saha, Birija Sankar Patro, Mrunesh Koli, Ganesh Pai, Jharna Ray, Sandip K Bandyopadhyay, Subrata Chattopadhyay
In view of the inadequacy of neuroblastoma treatment, five hydroxystilbenes and resveratrol (Resv) were screened for their cytotoxic property against human neuroblastoma cell lines. The mechanism of cytotoxic action of the most potent compound, trans-4,4'-dihydroxystilbene (DHS) was investigated in vitro using human neuroblastoma cell lines. DHS was also tested in a mouse xenograft model of human neuroblastoma tumor. The MTT, sub-G1, annexin V and clonogenic assays as well as microscopy established higher cytotoxicity of DHS than Resv to the IMR32 cell line...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28506283/prolactin-blocks-the-expression-of-receptor-activator-of-nuclear-factor-%C3%AE%C2%BAb-ligand-and-reduces-osteoclastogenesis-and-bone-loss-in-murine-inflammatory-arthritis
#6
Maria G Ledesma-Colunga, Norma Adán, Georgina Ortiz, Mariana Solís-Gutiérrez, Fernando López-Barrera, Gonzalo Martínez de la Escalera, Carmen Clapp
BACKGROUND: Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA). METHODS: Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor...
May 15, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28377978/long-term-treatment-with-odanacatib-maintains-normal-trabecular-biomechanical-properties-in-ovariectomized-adult-monkeys-as-demonstrated-by-micro-ct-based-finite-element-analysis
#7
Antonio Cabal, Donald S Williams, Richa Y Jayakar, Jingru Zhang, Swanand Sardesai, Le T Duong
The cathepsin K inhibitor odanacatib (ODN) is a potent and reversible inhibitor of osteoclastic resorption activity. This drug is currently under development for the treatment of postmenopausal osteoporosis. Previously, we described data on the treatment efficacy of ODN in a preclinical estrogen-deficient model of an ovariectomized (OVX) rhesus monkey using HR-pQCT based finite element analysis (FEA) in vivo estimates of bone strength on the distal radius. To support the bone safety profile of ODN, we report ex vivo data on the apparent and hard tissue biomechanical properties of the trabecular bone of vertebrae of animals after 20 months of dosing in three treatment groups: Vehicle (VEH), ODN (2 mg/kg/day), and ALN (30 μg/kg/week)...
June 2017: Bone Reports
https://www.readbyqxmd.com/read/28371355/bosutinib-an-src-inhibitor-induces-caspase-independent-cell-death-associated-with-permeabilization-of-lysosomal-membranes-in-melanoma-cells
#8
S Noguchi, S Shibutani, K Fukushima, T Mori, M Igase, T Mizuno
BACKGROUND: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. MATERIALS AND METHODS: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining...
March 28, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28326348/effects-of-odanacatib-on-bone-matrix-mineralization-in-rhesus-monkeys-are-similar-to-those-of-alendronate
#9
Barbara M Misof, Paul Roschger, Charles Chen, Maureen Pickarski, Phaedra Messmer, Klaus Klaushofer, Le T Duong
Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K which is an important enzyme for the degradation of collagen I. Aim of the present work was the head-to-head comparison between the effects of ODN and alendronate (ALN) on bone mineralization density distribution (BMDD), based on quantitative backscattered electron imaging in relation to changes in histomorphometric mineralizing surface per bone surface (MS/BS) in 12-22 years old ovariectomized rhesus monkeys. Trabecular and cortical BMDD derived parameters from vertebrae and proximal tibiae were compared among vehicle (VEH, n = 8), odanacatib low dose (ODN-L, n = 8), odanacatib high dose (ODN-H, n = 8), and alendronate (ALN, n = 6) treated animals...
December 2016: Bone Reports
https://www.readbyqxmd.com/read/28324911/synthesis-of-two-c-14-labeled-cathepsin-c-inhibitors-the-use-of-a-cyanide-to-displace-a-benzotriazole
#10
Lee Kingston, Jonas Bergare, Hans Lönn, Cecilia Ericsson, Gunnar Grönberg, Song Chen, Charles S Elmore
In support of the development of a new treatment for COPD, two C-14 labeled compounds were required for in vitro animal studies. The synthesis of nitrile [(14) C]-1 was completed in 3 steps from C-14 labeled 4-bromobenzonitrile in accord with the previously developed medicinal chemistry route. The second compound, 2, did not possess an arylnitrile as did 1 which made the synthetic design more complex. An advanced, unlabeled benzotriazole containing intermediate, 10, was synthesized in low yield over 3 steps and was subsequently reacted with K(14) CN to give a mixture of diastereomers 12...
March 21, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28322464/cathepsin-k-controls-cortical-bone-formation-by-degrading-periostin
#11
Nicolas Bonnet, Julia Brun, Jean-Charles Rousseau, Le T Duong, Serge L Ferrari
While inhibitors of bone resorption concomitantly reduce bone formation because of the coupling between osteoclasts and osteoblasts, inhibition or deletion of cathepsin k (CatK) stimulates bone formation despite decreasing resorption. The molecular mechanisms responsible for this increase in bone formation, particularly at periosteal surfaces where osteoclasts are relatively poor, remain unclear. Here we show that CatK pharmacological inhibition or deletion (Ctsk(-/-) mice) potentiates mechanotransduction signals mediating cortical bone formation...
March 21, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28321485/initial-autophagic-protection-switches-to-disruption-of-autophagic-flux-by-lysosomal-instability-during-cadmium-stress-accrual-in-renal-nrk-52e-cells
#12
W-K Lee, S Probst, M P Santoyo-Sánchez, W Al-Hamdani, I Diebels, J-K von Sivers, E Kerek, E J Prenner, F Thévenod
The renal proximal tubule (PT) is the major target of cadmium (Cd(2+)) toxicity where Cd(2+) causes stress and apoptosis. Autophagy is induced by cell stress, e.g., endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd(2+)-induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd(2+). Cd(2+)-induced autophagy in rat kidney PT cell line NRK-52E and its role in cell death was investigated...
March 20, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28304382/inhibition-of-cathepsin-k-promotes-osseointegration-of-titanium-implants-in-ovariectomised-rats
#13
Chun Yi, Ke-Yi Hao, Ting Ma, Ye Lin, Xi-Yuan Ge, Yu Zhang
The bone mineral deficiency in osteoporosis poses a threat to the long-term outcomes of endosseous implants. The inhibitors of cathepsin K (CatK) significantly affect bone turnover, bone mineral density (BMD) and bone strength in the patients with osteoporosis. Therefore, we hypothesised that the application of a CatK inhibitor (CatKI) could increase the osseointegration of endosseous implants under osteoporotic conditions. Odanacatib (ODN), a highly selective CatKI, was chosen as the experimental drug. Sixteen rats were randomised into 4 groups: sham, ovariectomy (OVX) with vehicle, OVX with low-dose ODN (5 mg/kg) and OVX with high-dose ODN (30 mg/kg)...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302039/bone-degeneration-inflammation-and-secondary-complications-of-arthritis-potential-targets-and-their-natural-inhibitors
#14
Mahadevappa Hemshekhar, Ram M Thushara, Somanatahpura K NaveenKumar, Paul Manoj, Mahalingam S Sundaram, Kempaiah Kemparaju, Kesturu S Girish
Arthritis is marked with joint deterioration that affects articular cartilage and subchondral bone. Though cartilage degradation is a major damage during arthritis, the subsequent bone loss cannot be neglected. Progress in the arthritis research has identified clinical importance of bone erosion in destructive arthritis. Studies have showed the key role played by osteoclasts and receptor activator of nuclear factor kappaB ligand (RANKL) signaling in bone erosion. Cathepsins and tartrate resistant acid phosphatase (TRAP) are considered key enzymatic factors contributing to bone erosion...
March 15, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28288319/synthesis-of-heterocyclic-ring-fused-tricyclic-diterpene-analogs-as-novel-inhibitors-of-rankl-induced-osteoclastogenesis-and-bone-resorption
#15
Gao Wei, Yalan Wu, Xiao-Long He, Ting Liu, Mingyao Liu, Jian Luo, Wen-Wei Qiu
A series of heterocyclic ring-fused tricyclic diterpene analogs were synthesized and their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated on bone marrow-derived monocytes (BMMs) by a cell based tartrate-resistant acid phosphatase (TRAP) activity assay. Among them, the most potent compound, 37 (QG368), showed 72.3% inhibition even at a low concentration of 0.1 μM, which was about 188-fold more potent than the lead compound. Cytotoxicity test on BMMs indicated that the inhibition on osteoclast differentiation of 37 did not result from its cytotoxicity...
May 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28287096/blockade-of-vascular-endothelial-growth-factor-receptors-by-tivozanib-has-potential-anti-tumour-effects-on-human-glioblastoma-cells
#16
Majid Momeny, Farima Moghaddaskho, Narges K Gortany, Hassan Yousefi, Zahra Sabourinejad, Ghazaleh Zarrinrad, Shahab Mirshahvaladi, Haniyeh Eyvani, Farinaz Barghi, Leila Ahmadinia, Mahmoud Ghazi-Khansari, Ahmad R Dehpour, Saeid Amanpour, Seyyed M Tavangar, Leila Dardaei, Amir H Emami, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28286757/effect-of-tumor-necrosis-factor-inhibitor-therapy-on-osteoclasts-precursors-in-rheumatoid-arthritis
#17
Inês P Perpétuo, Joana Caetano-Lopes, Ana Maria Rodrigues, Raquel Campanilho-Marques, Cristina Ponte, Helena Canhão, Mari Ainola, João E Fonseca
Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients. Methods. Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28270590/inhibition-of-mapk-erk-pathway-in%C3%A2-vivo-attenuates-aortic-valve-disease-processes-in-emilin1-deficient-mouse-model
#18
Charu Munjal, Anil G Jegga, Amy M Opoka, Ivan Stoilov, Russell A Norris, Craig J Thomas, J Michael Smith, Robert P Mecham, Giorgio M Bressan, Robert B Hinton
Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1-deficient mouse (Emilin1(-/-) ) is a model of latent AVD, characterized by activated TGFβ/MEK/p-Erk signaling and upregulated elastase activity...
March 2017: Physiological Reports
https://www.readbyqxmd.com/read/28236030/insights-from-molecular-modeling-into-the-selective-inhibition-of-cathepsin-s-by-its-inhibitor
#19
Sabahuddin Ahmad, Mohammad Imran Siddiqi
Cathepsin S has been demonstrated to play a crucial role in the remodeling of extracellular matrix proteins such as elastin and collagen, which in turn contribute to the structural integrity of the cardiovascular wall. Atherosclerotic lesions, aneurysm formation, plaque rupture, thrombosis, and calcification are some of the cardiovascular disorders related to cathepsin S. A highly selective inhibitor of human as well as animal cathepsin S, RO5444101, was recently reported to attenuate the progression of atherosclerotic lesions...
March 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28228366/leupeptazin-a-highly-modified-tripeptide-isolated-from-cultures-of-a-streptomyces-sp-inhibits-cathepsin-k
#20
Natasha Kruglyak, David E Williams, Henry Chen, Simon Law, Jadwiga Kaleta, Ivan Villanueva, Julian E Davies, Raymond J Andersen, Dieter Brömme
Using a human cathepsin K-targeting inhibitor screen, a new leupeptin analogue, leupeptazin (1), containing an unprecedented piperidinotriazine moiety, was isolated from a liquid culture of soil Streptomyces sp. IS2-4 collected in northern Italy. The structure of leupeptazin was established using HRESIMS as well as 1D and 2D NMR data. The inhibitory activity of the compound towards the collagenase cathepsin K was tested in vitro to reveal moderate activity with an inhibition constant, Ki, of 44μM.
February 5, 2017: Bioorganic & Medicinal Chemistry Letters
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