BALICATIB   中文名称: 巴利卡替

cathepsin K (IC50 = 22 nM); cathepsin L (IC50 = 48 nM); Cathepsin B (IC50 = 61 nM); cathepsin S (IC50 = 2900 nM)
Balicatib (0-10 µM) exhibits less than 1.5-fold accumulation of Type I collagen at concentrations up to 10 µM in human dermal fibroblasts[2].
Human cathepsin K (a cysteine protease), reversible inhibitor. [1]

Balicatib (0-10 µM) 在人真皮成纤维细胞中浓度高达 10 µM 时，I 型胶原蛋白的积累量不到 1.5 倍[2]。

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在使用兔破骨细胞于牛骨片上培养的功能性骨吸收实验中，Balicatib校正后的骨吸收IC₅₀为22 nM（根据兔和人Cat K效力差异计算）。其效力比odanacatib和L-873724低3至4倍。[2]
在使用人HepG2细胞（用于Cat B和L占据率）和Ramos细胞（用于Cat S占据率）的全细胞酶占据率实验中，Balicatib的IC₅₀值分别为61 nM (Cat B)、48 nM (Cat L) 和 2900 nM (Cat S)，表明其相对于Cat K的效力，细胞选择性较差。[2]
在使用原代人皮肤成纤维细胞（HDF）于三维胶原凝胶中培养的细胞模型中，用1-10 μM的Balicatib处理3天，导致细胞内I型胶原积累增加3至7倍（通过流式细胞术使用抗I型胶原抗体定量）。此效应归因于其溶酶体趋向性导致的多种组织蛋白酶抑制。[2]

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在使用兔破骨细胞于牛骨片上培养的功能性骨吸收实验中，Balicatib校正后的骨吸收IC₅₀为22 nM（根据兔和人Cat K效力差异计算）。其效力比odanacatib和L-873724低3至4倍。[2]
在使用人HepG2细胞（用于Cat B和L占据率）和Ramos细胞（用于Cat S占据率）的全细胞酶占据率实验中，Balicatib的IC₅₀值分别为61 nM (Cat B)、48 nM (Cat L) 和 2900 nM (Cat S)，表明其相对于Cat K的效力，细胞选择性较差。[2]
在使用原代人皮肤成纤维细胞（HDF）于三维胶原凝胶中培养的细胞模型中，用1-10 μM的Balicatib处理3天，导致细胞内I型胶原积累增加3至7倍（通过流式细胞术使用抗I型胶原抗体定量）。此效应归因于其溶酶体趋向性导致的多种组织蛋白酶抑制。[2]

Balicatib（0、3、10、50 mg/kg；口服灌胃；每天两次，持续 18 个月）抑制食蟹猴大部分部位的骨转换，略微阻止卵巢切除术带来的骨量变化，并刺激骨膜骨的形成[1]。

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研究使用了总共100只11-13岁的成年雌性食蟹猴（Macaca fascicularis）。80只动物接受双侧卵巢切除术（Ovx），20只接受假手术。去势动物分为四组：媒介物对照组（O组），以及三个Balicatib治疗组，分别接受3（低剂量，L组）、10（中剂量，M组）或50/30（高剂量，H组）mg/kg/天的剂量。由于食物消耗减少，高剂量在开始给药约1个月后从50 mg/kg/天降至30 mg/kg/天。[1]
Balicatib（AAE581马来酸盐）溶于无菌水。剂量溶液每周配制并冷藏。化合物于手术后第一天开始，通过鼻胃插管口服给药，每日两次，持续18个月。[1]
在氯胺酮镇静状态下，于基线时以及治疗的第3、6、9、12、15和18个月，通过双能X线吸收测定法（DXA）测量腰椎（L2-4）和全股骨的骨矿物质密度（BMD）。[1]
在治疗18个月后处死前，通过静脉注射钙黄绿素（4 mg/kg）进行骨形成标记，给药方案为（标记，间隔14天，标记，间隔7天，处死）。[1]
处死时，收集第二腰椎和右股骨，置于70%乙醇中固定，并进行静态和动态骨组织形态计量学分析，以评估矿化表面/骨表面（MS/BS）、矿化沉积率（MAR）和骨形成率/骨表面（BFR/BS）等参数。[1]

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研究使用了总共100只11-13岁的成年雌性食蟹猴（Macaca fascicularis）。80只动物接受双侧卵巢切除术（Ovx），20只接受假手术。去势动物分为四组：媒介物对照组（O组），以及三个Balicatib治疗组，分别接受3（低剂量，L组）、10（中剂量，M组）或50/30（高剂量，H组）mg/kg/天的剂量。由于食物消耗减少，高剂量在开始给药约1个月后从50 mg/kg/天降至30 mg/kg/天。[1]
Balicatib（AAE581马来酸盐）溶于无菌水。剂量溶液每周配制并冷藏。化合物于手术后第一天开始，通过鼻胃插管口服给药，每日两次，持续18个月。[1]
在氯胺酮镇静状态下，于基线时以及治疗的第3、6、9、12、15和18个月，通过双能X线吸收测定法（DXA）测量腰椎（L2-4）和全股骨的骨矿物质密度（BMD）。[1]
在治疗18个月后处死前，通过静脉注射钙黄绿素（4 mg/kg）进行骨形成标记，给药方案为（标记，间隔14天，标记，间隔7天，处死）。[1]
处死时，收集第二腰椎和右股骨，置于70%乙醇中固定，并进行静态和动态骨组织形态计量学分析，以评估矿化表面/骨表面（MS/BS）、矿化沉积率（MAR）和骨形成率/骨表面（BFR/BS）等参数。[1]

Balicatib对人Cat K及脱靶组织蛋白酶（B, L, S）的体外活性（IC₅₀）使用纯化酶实验测定。实验条件参考了先前的出版物。IC₅₀值代表至少三次滴定的平均值，标准偏差通常在IC₅₀值的35%以内。[2]

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Balicatib对人Cat K及脱靶组织蛋白酶（B, L, S）的体外活性（IC₅₀）使用纯化酶实验测定。实验条件参考了先前的出版物。IC₅₀值代表至少三次滴定的平均值，标准偏差通常在IC₅₀值的35%以内。[2]

Balicatib在功能性骨吸收实验中的效力通过兔破骨细胞在牛骨切片上培养进行评估。该实验测量破骨细胞骨吸收陷窝形成的抑制情况。[2]
进行了全细胞酶占据率实验，以在更生理相关的背景下评估选择性。使用人HepG2细胞评估Cat B和Cat L的占据率，使用人Ramos B细胞评估Cat S的占据率。细胞用化合物处理、裂解，并使用基于活性的探针测量酶占据率。[2]
使用原代人皮肤成纤维细胞（HDF）评估了对细胞内胶原积累的影响。成纤维细胞在三维胶原凝胶内培养。在培养的最后3天加入抑制剂。随后，用胶原酶处理将细胞从胶原基质中提取出来，然后固定、透化，并使用特异性单克隆一抗和FITC标记的二抗对细胞内I型胶原进行染色。通过流式细胞术定量每个细胞的平均荧光强度，该强度与细胞内胶原水平相对应。[2]

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Balicatib在功能性骨吸收实验中的效力通过兔破骨细胞在牛骨切片上培养进行评估。该实验测量破骨细胞骨吸收陷窝形成的抑制情况。[2]
进行了全细胞酶占据率实验，以在更生理相关的背景下评估选择性。使用人HepG2细胞评估Cat B和Cat L的占据率，使用人Ramos B细胞评估Cat S的占据率。细胞用化合物处理、裂解，并使用基于活性的探针测量酶占据率。[2]
使用原代人皮肤成纤维细胞（HDF）评估了对细胞内胶原积累的影响。成纤维细胞在三维胶原凝胶内培养。在培养的最后3天加入抑制剂。随后，用胶原酶处理将细胞从胶原基质中提取出来，然后固定、透化，并使用特异性单克隆一抗和FITC标记的二抗对细胞内I型胶原进行染色。通过流式细胞术定量每个细胞的平均荧光强度，该强度与细胞内胶原水平相对应。[2]

11-13 years, female cynomolgus monkeys (Macaca fascicularis)[1]
0, 3, 10, 50 mg/kg
Oral gavage; twice daily for 18 months

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A total of 100 adult female cynomolgus monkeys (Macaca fascicularis) aged 11-13 years were used. Eighty animals underwent bilateral ovariectomy (Ovx), and 20 underwent sham surgery. Ovx animals were divided into four groups: vehicle control (Group O), and three Balicatib treatment groups receiving 3 (Low, L), 10 (Medium, M), or 50/30 (High, H) mg/kg/day. The high dose was reduced from 50 to 30 mg/kg/day approximately 1 month after initiation due to reduced food consumption. [1]
Balicatib (AAE581 maleate) was dissolved in sterile water. Dose solutions were prepared weekly and refrigerated. The compound was administered orally twice daily via nasogastric intubation, starting the day after surgery, for 18 months. [1]
Bone mineral density (BMD) of the lumbar spine (L2-4) and whole femur was measured by DXA at baseline and at 3, 6, 9, 12, 15, and 18 months under ketamine sedation. [1]
Prior to necropsy at 18 months, bone formation was labeled by intravenous administration of calcein (4 mg/kg) on a schedule (label, 14-day interval, label, 7-day interval, necropsy). [1]
At necropsy, the second lumbar vertebra and right femur were collected, fixed in 70% ethanol, and processed for static and dynamic bone histomorphometry to assess parameters such as mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS). [1]

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A total of 100 adult female cynomolgus monkeys (Macaca fascicularis) aged 11-13 years were used. Eighty animals underwent bilateral ovariectomy (Ovx), and 20 underwent sham surgery. Ovx animals were divided into four groups: vehicle control (Group O), and three Balicatib treatment groups receiving 3 (Low, L), 10 (Medium, M), or 50/30 (High, H) mg/kg/day. The high dose was reduced from 50 to 30 mg/kg/day approximately 1 month after initiation due to reduced food consumption. [1]
Balicatib (AAE581 maleate) was dissolved in sterile water. Dose solutions were prepared weekly and refrigerated. The compound was administered orally twice daily via nasogastric intubation, starting the day after surgery, for 18 months. [1]
Bone mineral density (BMD) of the lumbar spine (L2-4) and whole femur was measured by DXA at baseline and at 3, 6, 9, 12, 15, and 18 months under ketamine sedation. [1]
Prior to necropsy at 18 months, bone formation was labeled by intravenous administration of calcein (4 mg/kg) on a schedule (label, 14-day interval, label, 7-day interval, necropsy). [1]
At necropsy, the second lumbar vertebra and right femur were collected, fixed in 70% ethanol, and processed for static and dynamic bone histomorphometry to assess parameters such as mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS). [1]

Balicatib is described as a lysosomotropic compound. Its basic and lipophilic nature leads to accumulation in lysosomes (pH 4-5), which increases its apparent potency against off-target cathepsins also located in lysosomes in cellular assays. [2]

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Balicatib is described as a lysosomotropic compound. Its basic and lipophilic nature leads to accumulation in lysosomes (pH 4-5), which increases its apparent potency against off-target cathepsins also located in lysosomes in cellular assays. [2]

Food consumption fell abruptly in the high-dose group (50 mg/kg/day) upon initiation of dosing, reaching a nadir at week 4, leading to a dose reduction to 30 mg/kg/day. [1]
Body weight gain during the study was significantly lower in the high-dose group compared to ovariectomized controls. [1]
One animal in the high-dose group died during month 16 following clinical signs of hind limb paralysis. Retrospectively, this animal had abnormalities including high serum osteocalcin and CTx levels since baseline and steady spinal bone loss. [1]

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Food consumption fell abruptly in the high-dose group (50 mg/kg/day) upon initiation of dosing, reaching a nadir at week 4, leading to a dose reduction to 30 mg/kg/day. [1]
Body weight gain during the study was significantly lower in the high-dose group compared to ovariectomized controls. [1]
One animal in the high-dose group died during month 16 following clinical signs of hind limb paralysis. Retrospectively, this animal had abnormalities including high serum osteocalcin and CTx levels since baseline and steady spinal bone loss. [1]

[1]. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int. 2012 Jan;23(1):339-49.

[2]. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8.

Balicatib has been used in trials studying the treatment of Osteoporosis and Knee Osteoarthritis.

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Balicatib is a cathepsin K inhibitor developed for the treatment of osteoporosis. Unlike most bone resorption inhibitors (e.g., bisphosphonates), Balicatib demonstrated a unique ability to stimulate periosteal bone formation in this long-term primate study, suggesting it may have anabolic properties in addition to its anti-resorptive effects. [1]
The study suggests that the stimulatory effect on periosteal bone formation, combined with weak inhibition of endocortical bone formation in the femur, may explain why Balicatib increased femur bone mass more effectively than spinal bone mass. [1]

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Balicatib is a cathepsin K inhibitor developed for the treatment of osteoporosis. Unlike most bone resorption inhibitors (e.g., bisphosphonates), Balicatib demonstrated a unique ability to stimulate periosteal bone formation in this long-term primate study, suggesting it may have anabolic properties in addition to its anti-resorptive effects. [1]
The study suggests that the stimulatory effect on periosteal bone formation, combined with weak inhibition of endocortical bone formation in the femur, may explain why Balicatib increased femur bone mass more effectively than spinal bone mass. [1]

C23H33N5O2

411.5404

411.263

C, 67.12; H, 8.08; N, 17.02; O, 7.78

354813-19-7

354813-19-7

10201696

white to off-white solid powder

1.2±0.1 g/cm3

687.4±55.0 °C at 760 mmHg

369.5±31.5 °C

0.0±2.1 mmHg at 25°C

1.590

1.56

91.96

2

5

7

30

621

0

O=C(C1(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])N([H])C(C1C([H])=C([H])C(=C([H])C=1[H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])[H])C([H])([H])C1([H])[H])=O)N([H])C([H])([H])C#N

LLCRBOWRJOUJAE-UHFFFAOYSA-N

InChI=1S/C23H33N5O2/c1-2-14-27-15-17-28(18-16-27)20-8-6-19(7-9-20)21(29)26-23(10-4-3-5-11-23)22(30)25-13-12-24/h6-9H,2-5,10-11,13-18H2,1H3,(H,25,30)(H,26,29)

N-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(4-propylpiperazin-1-yl)benzamide

Balicatib; AAE-581; AAE 581; AAE581

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 75~82 mg/mL (182.2~199.3 mM)
Ethanol: ~3 mg/mL (~7.3 mM)

配方 1 中的溶解度: ≥ 3.75 mg/mL (9.11 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 37.5 mg/mL 澄清的 DMSO 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL 生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 3.75 mg/mL (9.11 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 37.5 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。