ONO-5334
目录号 : GC61158
ONO-5334是一种强效、选择性和口服活性的组织蛋白酶K(cathepsinK)抑制剂，对人、兔和大鼠组织蛋白酶K的作用值分别为0.10nM、0.049nM和0.85nM。ONO-5334是一种有效的抗SAR-COV-2病毒活性的抗病毒化合物，其EC50值为500nM。ONO-5334有潜力用于骨质疏松症以及COVID-19的相关研究。
Cas No.:868273-90-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ONO-5334 is a potent, selective and orally active cathepsin K inhibitor with Ki values of 0.10 nM, 0.049 nM and 0.85 nM for human, rabbit and rat cathepsin K, respectively. ONO 5334 is an effective antiviral compound against SAR-COV-2 virus activity with an EC50 value of 500 nM. ONO-5334 has the potential for the study of osteoporosis and COVID-19 disease[1].
ONO-5334 has inhibitory effects on human cathepsin S, human cathepsin L, human cathepsin B, porcine calpain Ι and porcine calpain II with Ki values of 0.83 nM, 1.7 nM, 32 nM, 82 nM and 69 nM, respectively[1].ONO-5334 (0.1-1 μM; 24 hours) suppresses human osteoclast-mediated bone resorption. It potently reduces osteoclast-mediated release of CTX from bone slices as a dose dependent manner[1].ONO-5334 (0-10 μM; pre-treated for 16 h) inhibits antiviral activities in a discernable dose-dependent manner in Vero E6 cells by designed to capture multicycle replication, exhibiting an EC50 value of 0.5 μM[2]/ Cell Viability Assay[2] Cell Line: Vero E6 cells
ONO-5334 (oral administration; 0.12-15 mg/kg; single dose) can dose-dependently reduce PTHrP-induced increase in plasma calcium with significant effect (86% reduction) at 15 mg/kg. It also reduces PTHrP-induced increase in plasma CTX level in TPTX rats by 90% at 15 mg/kg[1].ONO-5334 (oral administration; 0.3-30 mg/kg; 7 consecutive days) at 3 mg/kg or 30 mg/kg significantly decreases CTX (a bone resorption marker) concentration. On day 7, the reduction in serum CTX concentration by ONO-5334 at 3 mg/kg and 30 mg/kg was 62% and 79%, respectively[1]. Animal Model: Monkey[1]
[1]. Ochi Y, et al. Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone. 2011 Dec;49(6):1351-6. [2]. Laura Riva, et al.A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. bioRxiv. 2020 Apr 17;2020.04.16.044016.
| Cas No. | 868273-90-9 | SDF | |
| Canonical SMILES | O=C(C(N/N=C(SC[C@H]1C)/N1C)=O)[C@H](C2CCOCC2)NC(C3CCCCCC3)=O | ||
| 分子式 | C21H34N4O4S | 分子量 | 438.58 |
| 溶解度 | DMSO : 50 mg/mL (114.00 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2801 mL | 11.4004 mL | 22.8009 mL |
| 5 mM | 0.456 mL | 2.2801 mL | 4.5602 mL |
| 10 mM | 0.228 mL | 1.14 mL | 2.2801 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys
Int J Rheumatol 2019 Feb 17;2019:5710340.PMID:30906325DOI:10.1155/2019/5710340.
We examined whether the cathepsin K inhibitor, ONO-5334, administered alone or in combination with methotrexate (MTX), could ameliorate joint destruction evoked by collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine type II collagen. ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of C-terminal telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) were measured. Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this collagen-induced arthritis monkey model. ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group. ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively. After treatment with ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion, ONO-5334 prevented joint destruction but not joint inflammation in this monkey CIA model. Concomitant use of ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore, ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of rheumatoid arthritis.
ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats
J Bone Miner Metab 2014 Nov;32(6):645-52.PMID:24317478DOI:10.1007/s00774-013-0542-x.
This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis.
Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism
Bone 2011 Dec;49(6):1351-6.PMID:21982869DOI:10.1016/j.bone.2011.09.041.
In the present study, we examined the in vitro and in vivo pharmacological effects of ONO-5334, a novel inhibitor of cathepsin K, on bone metabolism. In vitro experiments indicated that ONO-5334 is a potent inhibitor of cathepsin K with Ki value of 0.1 nM. Although this compound inhibited other cysteine proteases, such as cathepsin S, L and B, its inhibitory activity for these enzymes was 8 to 320 fold lower than that for cathepsin K. ONO-5334 also inhibited human osteoclasts bone resorption in vitro at a concentration more than 100 fold lower than that of alendronate, a bisphosphonate. While alendronate disrupted actin ring and induced pyknotic nuclei in osteoclasts, ONO-5334 did not have such effects, suggesting that this compound does not affect osteoclasts viability. In in vivo experiments, oral administration of ONO-5334 dose-dependently reduced plasma calcium level increased by parathyroid hormone related peptide in thyroparathyroidectomized rats. Furthermore, in vivo experiment using normal monkeys demonstrated that ONO-5334 decreases serum and urine C-telopeptide of type I collagen level, a bone resorption marker, soon after oral dosing. These levels were consistently decreased below pre-dose levels by repeated oral dosing with ONO-5334 for 7 days. ONO-5334 on the other hand did not affect bone formation markers, serum osteocalcin and bone specific alkaline phosphatase. These findings indicate that ONO-5334 is a specific inhibitor for cathepsin K and thus may be a novel therapeutic agent for metabolic bone diseases.
Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study
J Bone Miner Res 2014 Feb;29(2):458-66.PMID:23873670DOI:10.1002/jbmr.2047.
Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO-5334 300 mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO-5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation.
[New approach for osteoporosis treatment: cathepsin K inhibitor, ONO-5334]
Clin Calcium 2011 Jan;21(1):64-9.PMID:21187596doi
ONO-5334, an orally-administered low-molecular compound, is a selective synthetic inhibitor of cathepsin K which is specifically expressed in osteoclasts and has a critical role in bone-collagen degradation. ONO-5334 is being developed by Ono Pharmaceutical Co., Ltd. as a possible therapeutic agent for osteoporosis. ONO-5334 has been shown to prevent the decrease in bone mineral density (BMD) in the ovariectomized cynomolgus monkey osteoporosis model. In a 12-month clinical study with postmenopausal osteopenia or osteoporosis, ONO-5334 showed a significant increase in BMD compared with placebo and a similar magnitude of suppression on bone resorption compared with the current well known anti-resorptive agents, bisphosphonates, but with little or no suppression on bone formation. There were no clinically relevant safety concerns identified in this study. Whether this mechanism of action may result in more potent anti-fracture efficacy accompanied by better bone quality in long term use of ONO-5334 is of significant interest.