Relacatib
(Synonyms: SB-462795) 目录号 : GC63856
Relacatib (SB-462795) 是一种新的，有效的口服活性的人组织蛋白酶 K, L 和 V (cathepsins K, L, V) 的抑制剂，其Ki 值分别为 41, 68 和 53 pM。Relacatib 原位抑制人破骨细胞内源性组织蛋白酶 K 和人破骨细胞介导的骨吸收，IC50 值分别为 45 nM 和 70 nM。Relacatib 对体外人体组织骨吸收的抑制作用，以及对食蟹猴体内骨吸收有抑制作用。
Cas No.:362505-84-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Relacatib (SB-462795) is a novel, potent, and orally active inhibitor of human cathepsins K, L, and V with Ki values of 41 pM, 68 pM, and 53 pM, respectively. Relacatib inhibits endogenous cathepsin K in situ in human osteoclasts and human osteoclast-mediated bone resorption with IC50 values of 45 nM and 70 nM, respectively. Relacatib inhibits bone resorption in vitro in human tissue as well as in cynomolgus monkeys in vivo[1][2].
Relacatib are incubated with human osteoclastoma-derived osteoclasts seeded onto bovine cortical bone slices in vitro biological activity, it shows inhibitory potency with Ki values of 0.041 nM, 0.068 nM,0.063 nM,1.6 nM,and 13 nM against human cathepsin K, cathepsin L, cathepsin V, cathepsin S and cathepsin B, respectively in the assay[1]. Relacatib is against Monkey cathepsin K, cathepsin L,cathepsin V and cathepsin B with Ki values of 0.041 nM, 0.28 nM, 0.72 nM and 11nM, respectively. Relacatib is against mouse cathepsin L and rat cathepsin L with Ki values of 0.20 nM and 0.17 nM, respectively[2].
Relacatib (1-2 mg/kg 0.5 h intravenous infusion; 2-4 mg/kg oral bolus gavage) exhibits T1/2, CL or Vdss with 109 mins, 19.5 mL/min/kg, or 1.86 L/kg in male Sprague-Dawley rats and 168 mins, 11.7 mL/min/kg, and 1.79 L/kg in monkeys, respectively in a PK iv/po crossover studies. The oral bioavailability of Relacatib is 28% in the monkey and 89.4% in the rats[1].SB-462795 (subcutaneous injection; 12 mg/kg; blood sample is drawn 1.5, 4, 24, 48, and 72 h post dose administration) significantly inhibits resorption as assessed by two markers of bone resorption,the N- (NTx) and C-telopeptides (CTx) of type I collagen measured in serum. SB-462795 does not exhibit difference of serum osteocalcin (a biomarker of osteoblast activity) between SB-462795 and vehicle treated animalsexcept for the 48 h time point where a significant reduction (42% lower than baseline vs. 18% lower than baseline with vehicle treatment)[2].
[1]. Dennis S Yamashita, et al. Structure Activity Relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one Cathepsin K Inhibitors.J Med Chem
[2]. S Kumar, et al.A Highly Potent Inhibitor of Cathepsin K (Relacatib) Reduces Biomarkers of Bone Resorption Both in Vitro and in an Acute Model of Elevated Bone Turnover in Vivo in Monkeys.Bone. 2007 Jan;40(1):122-31.
| Cas No. | 362505-84-8 | SDF | Download SDF |
| 别名 | SB-462795 | ||
| 分子式 | C27H32N4O6S | 分子量 | 540.63 |
| 溶解度 | 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。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8497 mL | 9.2485 mL | 18.4969 mL |
| 5 mM | 0.3699 mL | 1.8497 mL | 3.6994 mL |
| 10 mM | 0.185 mL | 0.9248 mL | 1.8497 mL |
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2.
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[Cathepsin K antagonists: preclinical and clinical data]
Wien Med Wochenschr 2015 Feb;165(3-4):65-70.PMID:25572547DOI:10.1007/s10354-014-0336-3.
Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and Relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.
Cathepsin K Inhibition: A New Mechanism for the Treatment of Osteoporosis
Calcif Tissue Int 2016 Apr;98(4):381-97.PMID:26335104DOI:10.1007/s00223-015-0051-0.
Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage. This in turn maintains the signals for bone formation, and perhaps may even increase bone formation on some cortical surfaces. Several CatK inhibitors, including Relacatib, balicatib, odanacatib and ONO-5334 had entered clinical development for metabolic bone disorders with increased bone resorption, such as postmenopausal osteoporosis. However, odanacatib (ODN) is the only candidate continuing in development. ODN is a highly selective oral CatK inhibitor dosed once-weekly in humans. In a Phase 2 clinical trial, postmenopausal women treated with ODN had sustained reductions of bone resorption markers, while bone formation markers returned to normal after an initial decline within the first 2 years on treatment. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. ODN has also been demonstrated to improve bone mass in women with postmenopausal osteoporosis previously treated with alendronate and in men with osteoporosis. ODN is currently in a worldwide Phase 3 fracture outcome trial for the treatment of postmenopausal osteoporosis with interim results supporting its anti-fracture efficacy at the spine, hip and non-vertebral sites.
Treatment with a potent cathepsin K inhibitor preserves cortical and trabecular bone mass in ovariectomized monkeys
Calcif Tissue Int 2009 Oct;85(4):344-55.PMID:19763376DOI:10.1007/s00223-009-9279-x.
The cysteine protease cathepsin K is involved in osteoclast-mediated bone resorption. We evaluated the effect of daily oral dosing of an inhibitor of human cathepsin K (SB-462795 [Relacatib]) for 9 months on bone turnover, mass, and architecture in estrogen-deficient cynomolgus monkeys. Ovariectomized animals were treated orally with Relacatib at 1, 3, or 10 mg/kg/day, or oral vehicle plus alendronate at 0.05 mg/kg by IV injection once every 2 weeks. The control groups, ovariectomized and sham-ovariectomized animals, received vehicle (all groups n = 20 animals). Samples for biomarker analysis were collected at various times, bone mass changes were evaluated at 6 and 9 months of treatment, and histomorphometric analysis was performed at 9 months. Relacatib significantly reduced urinary N-telopeptide excretion within 1 week of treatment at all dose levels, an effect that was maintained at the highest dose level. At some time points bone formation markers were elevated at the lowest dose of Relacatib. Animals treated with Relacatib had dose-dependent preservation of areal bone mineral density reaching statistical significance in distal femur. In femur neck there was significant preservation of total volumetric BMD (vBMD) by Relacatib. By histomorphometry, Relacatib reduced indices of bone resorption and formation at cancellous sites as did alendronate. In cortical bone, osteonal bone formation rate was reduced by alendronate but preserved at low and medium doses of Relacatib. Thus, Relacatib preserved cortical and cancellous bone mass in ovariectomized monkeys.
A highly potent inhibitor of cathepsin K (Relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys
Bone 2007 Jan;40(1):122-31.PMID:16962401DOI:10.1016/j.bone.2006.07.015.
Cathepsin K is an osteoclast-derived cysteine protease that has been implicated as playing a major role in bone resorption. A substantial body of evidence indicates that cathepsin K is critical in osteoclast-mediated bone resorption and suggests that its pharmacological inhibition should result in inhibition of bone resorption in vivo. Here we report the pharmacological characterization of SB-462795 (Relacatib) as a potent and orally bioavailable small molecule inhibitor of cathepsin K that inhibits bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys. SB-462795 is a potent inhibitor of human cathepsins K, L, and V (K(i, app)=41, 68, and 53 pM, respectively) that exhibits 39-300-fold selectivity over other cathepsins. SB-462795 inhibited endogenous cathepsin K in situ in human osteoclasts and human osteoclast-mediated bone resorption with IC50 values of approximately 45 nM and approximately 70 nM, respectively. The anti-resorptive potential of SB-462795 was evaluated in normal as well as medically ovariectomized (Ovx) female cynomolgus monkeys. Serum levels of the C- and N-terminal telopeptides of Type I collagen (CTx and NTx, respectively) and urinary levels of NTx were monitored as biomarkers of bone resorption. Administration of SB-462795 to medically ovariectomized or normal monkeys resulted in an acute reduction in both serum and urinary markers of bone resorption within 1.5 h after dosing, and this effect lasted up to 48 h depending on the dose administered. Our data indicate that SB-462795 potently inhibits human cathepsin K in osteoclasts, resulting in a rapid inhibition of bone resorption both in vitro and in vivo in the monkey. These studies also demonstrate the therapeutic potential of Relacatib in the treatment of postmenopausal osteoporosis and serves to model the planned clinical trials in human subjects.
The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Bioorg Med Chem Lett 2008 Feb 1;18(3):923-8.PMID:18226527DOI:10.1016/j.bmcl.2007.12.047.
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and Relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.