BM635
目录号 : GC32204
BM635是MmpL3的抑制剂，具有出色的抗分歧杆菌活性。抑制结合分歧杆菌H37Rv的MIC50值为0.12μM。
Cas No.:1493762-74-5
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
Cell experiment: | The measurement of the minimum inhibitory concentration (MIC) for each tested compounds (including BM635) are performed in 96 wells flat-bottom, polystyrene microtiter plates. Ten two-fold drug dilutions in neat DMSO starting at 200 µM are performed. Five µL of these drug solutions are added to 95 µL of Middlebrook 7H9 medium. Isoniazid is used as a positive control, 8 two-fold dilutions of Isoniazid starting at 160 µg/mL are prepared and 5 µL of this control curve is added to 95 µL of Middlebrook 7H9 medium. Five µL of neat DMSO are added 95 µL of Middlebrook 7H9 medium in row 12 (growth and Blank controls). The inoculum is standardized to approximately 1×107 cfu/mL and diluted 1 in 100 in Middlebrook 7H9 broth to produce the final inoculum of H37Rv strain. One hundred µL of this inoculum is added to the entire plate but G-12 and H-12 wells (Blank controls). All plates are placed in a sealed box to prevent drying out of the peripheral wells and they are incubated at 37°C without shaking for six days. A resazurin solution is prepared by dissolving one tablet of resazurin in 30 mL sterile PBS (phosphate buffered saline). Of this solution, 25 µL are added to each well. Fluorescence is measured after 48 hours to determine the MIC value[1]. |
Animal experiment: | Mouse: Nine (one per dose) 8-10 week old B6 female mice are infected by intratracheal route with 105CFU H37Rv per mouse suspended in 50 µL phosphate buffer saline. BM635 is administered once a day at nine doses ranging from 40 to 300 mg/kg from day 1 to day 8 after infection, and 24 hours after the last dose the mice are sacrificed. To measure the infection burden in lungs, all lobes are aseptically removed and homogenized. The homogenates are supplemented with 5% glycerol and stored frozen (−80°C) until plating. Plates (10%OADC-7H11 medium) are incubated for 14 days at 37°C[1]. |
References: [1]. Poce G, et al. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One. 2013;8(2):e56980. | |
BM635 is a MmpL3 inhibitor with outstanding anti-mycobacterial activity. BM635 has an MIC50 of 0.12 μM against M. tuberculosis H37Rv.
BM635 has potent MIC (0.12 µM), Tox50:MIC ratio of >100, and good microsomal stability in mice (1.4 mL/min/g). When tested in an acute murine infection model at multiple doses, BM635 exhibits potent anti-tubercular activity, with an ED99 of 49 mg/Kg (IC95%: 43-54 mg/Kg)[1]. The half-life in vivo of BM635 is 1h, allowing a reasonable maximum concentration (Cmax=1.62 μM) and a moderate bioavailability (46%). Its poor aqueous solubility together with its high lipophilicity leads to low exposure in vivo[2].
[1]. Poce G, et al. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One. 2013;8(2):e56980. [2]. Poce G, et al. Pharmaceutical salt of BM635 with improved bioavailability. Eur J Pharm Sci. 2017 Mar 1;99:17-23.
| Cas No. | 1493762-74-5 | SDF | |
| Canonical SMILES | CC(C1=CC=C(C2=CC(CN3CCOCC3)=C(C)N2C4=CC=C(F)C=C4)C=C1)C | ||
| 分子式 | C25H29FN2O | 分子量 | 392.51 |
| 溶解度 | DMSO : 31 mg/mL (78.98 mM) | 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 | 2.5477 mL | 12.7385 mL | 25.4771 mL |
| 5 mM | 0.5095 mL | 2.5477 mL | 5.0954 mL |
| 10 mM | 0.2548 mL | 1.2739 mL | 2.5477 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。
Pharmaceutical salt of BM635 with improved bioavailability
Eur J Pharm Sci 2017 Mar 1;99:17-23.PMID:27939618DOI:10.1016/j.ejps.2016.12.003.
BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12μM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1h, allowing a reasonable maximum concentration (Cmax=1.62μM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes.
In vivo potent BM635 analogue with improved drug-like properties
Eur J Med Chem 2018 Feb 10;145:539-550.PMID:29335214DOI:10.1016/j.ejmech.2017.12.075.
BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.
Nano-Based Drug Delivery Systems of Potent MmpL3 Inhibitors for Tuberculosis Treatment
Pharmaceutics 2022 Mar 10;14(3):610.PMID:35335983DOI:10.3390/pharmaceutics14030610.
Tuberculosis remains one of the world's deadliest infectious diseases, accounting for nearly 1.3 million deaths every year. Tuberculosis treatment is challenging because of the toxicity, decreased bioavailability at the target site of the conventional drugs and, most importantly, low adherence of patients; this leads to drug resistance. Here, we describe the development of suitable nanocarriers with specific physicochemical properties to efficiently deliver two potent antimycobacterial compounds. We prepared nanoemulsions and niosomes formulations and loaded them with two different MmpL3 inhibitors previously identified (NEs + BM635 and NIs + BM859). NEs + BM635 and NIs + BM859 were deeply characterized for their physicochemical properties and anti-mycobacterial activity. NEs + BM635 and NIs + BM859 showed good hydrodynamic diameter, ζ-Potential, PDI, drug-entrapment efficiency, polarity, and microviscosity and stability. Even though both formulations proved to perform well, only NIs + BM859 showed potent antimycobacterial activity against M. tuberculosis (MIC = 0.6 µM) compared to that of the free compound. This is most probably caused by the fact that BM635, being highly hydrophobic, encounters maximum hindrance in diffusion, whereas BM859, characterized by high solubility in aqueous medium (152 µM), diffuses more easily. The niosomal formulation described in this work may be a useful therapeutic tool for tuberculosis treatment, and further studies will follow to characterize the in vivo behavior of the formulation.