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Cathepsin k inhibitors

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https://www.readbyqxmd.com/read/28326348/effects-of-odanacatib-on-bone-matrix-mineralization-in-rhesus-monkeys-are-similar-to-those-of-alendronate
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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...
March 9, 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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28223547/cabozantinib-targets-bone-microenvironment-modulating-human-osteoclast-and-osteoblast-functions
#13
Marco Fioramonti, Daniele Santini, Michele Iuliani, Giulia Ribelli, Paolo Manca, Nicola Papapietro, Filippo Spiezia, Bruno Vincenzi, Vincenzo Denaro, Antonio Russo, Giuseppe Tonini, Francesco Pantano
Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal disease-related endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts.Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28222138/anti-trypanosomal-activity-of-non-peptidic-nitrile-based-cysteine-protease-inhibitors
#14
Antonio C B Burtoloso, Sérgio de Albuquerque, Mark Furber, Juliana C Gomes, Cristiana Gonçalez, Peter W Kenny, Andrei Leitão, Carlos A Montanari, José Carlos Quilles, Jean F R Ribeiro, Josmar R Rocha
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay...
February 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28220210/applicability-of-in-vitro-in-vivo-translation-of-cathepsin-k-inhibition-from-animal-species-to-human-with-the-use-of-free-drug-hypothesis
#15
Bennett Ma, Bin Luo, Danielle H Euler, Tara E Cusick, Gregg Wesolowski, Helmut Glantschnig, Le T Duong, Yangsi Ou, Steven S Carroll, Laura S Lubbers
The correlation of in vitro inhibition of cathepsin K (CatK) activity and in vivo suppression of collagen I biomarkers was examined with three selective CatK inhibitors to explore the potential translatability from animal species to human. These inhibitors exhibited good in vitro potencies toward recombinant CatK enzymes across species, with IC50 values ranging from 0.20 to 6.1 nM. In vivo studies were conducted in animal species following multiple-day dosing of the CatK inhibitors to achieve steady-state plasma drug concentration-time profiles...
February 20, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28217533/role-of-odanacatib-in-reducing-bone-loss-due-to-endodontic-disease-an-overview
#16
REVIEW
Rachana Bahuguna, Atul Jain, Suleman Abbas Khan, M S Arvind
AIMS AND OBJECTIVES: Through a comprehensive literature review, this article provides an overview of the potential role of odanacatib (ODN) in reducing bone loss due to endodontic disease. MATERIALS AND METHODS: A literature review was performed in PubMed Central, MEDLINE, Cochrane Library, and EBSCO databases. The articles identified included those published between 2002 and 2016. Based on the predetermined inclusion and exclusion criteria, out of 237 articles found, 50 were selected for this review...
December 2016: Journal of International Society of Preventive & Community Dentistry
https://www.readbyqxmd.com/read/28209487/lipoxin-a4-suppresses-osteoclastogenesis-in-raw264-7-cells-and-prevents-ovariectomy-induced-bone-loss
#17
Changyu Liu, Hanfeng Guan, Cong Cai, Feng Li, Jun Xiao
Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4)...
March 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28199790/an-integrated-microfluidic-processor-for-dna-encoded-combinatorial-library-functional-screening
#18
Andrew B MacConnell, Alexander K Price, Brian M Paegel
DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits...
March 13, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28196851/inhibition-of-lipopolysaccharide-induced-osteoclast-formation-and-bone-resorption-in-vitro-and-in-vivo-by-cysteine-proteinase-inhibitors
#19
Fredrik Strålberg, Ali Kassem, Franciszek Kasprzykowski, Magnus Abrahamson, Anders Grubb, Catharina Lindholm, Ulf H Lerner
Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginyl-leucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-κB ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors...
February 14, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28174118/molecular-and-structural-characterization-of-novel-cystatins-from-the-taiga-tick-ixodes-persulcatus
#20
Carolina K Rangel, Luís F Parizi, Gabriela A Sabadin, Evenilton P Costa, Nelilma C Romeiro, Masayoshi Isezaki, Naftaly W Githaka, Adriana Seixas, Carlos Logullo, Satoru Konnai, Kazuhiko Ohashi, Itabajara da Silva Vaz
Cystatins are cysteine peptidase inhibitors that in ticks mediate processes such as blood feeding and digestion. The ixodid tick Ixodes persulcatus is endemic to the Eurasia, where it is the principal vector of Lyme borreliosis. To date, no I. persulcatus cystatin has been characterized. In the present work, we describe three novel cystatins from I. persulcatus, named JpIpcys2a, JpIpcys2b and JpIpcys2c. In addition, the potential of tick cystatins as cross-protective antigens was evaluated by vaccination of hamsters using BrBmcys2c, a cystatin from Rhipicephalus microplus, against I...
January 31, 2017: Ticks and Tick-borne Diseases
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