BMS-986202
目录号 : GC62491
BMS-986202 是一种有效的，选择性的，具有口服活性的 Tyk2 抑制剂，可与 Tyk2 JH2 结合，IC50 为 0.19 nM，Ki 为 0.02 nM。BMS-986202 对包括 Jak 家族成员在内的其他激酶具有高度选择性。BMS-986202 还是 CYP2C19 的弱抑制剂，IC50 为 14 μM。BMS-986202 可用于 IL-23 驱动的棘皮症，抗 CD40 诱导的结肠炎和自发性狼疮的研究。
Cas No.:1771691-34-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BMS-986202 is a potent, selective and orally active Tyk2 inhibitor that binds to Tyk2 JH2 with an IC50 of 0.19 nM and a Ki of 0.02 nM. BMS-986202 is remarkably selective over other kinases including Jak family members. BMS-986202 is also a weak inhibitor of CYP2C19 with an IC50 of 14 μM. BMS-986202 can be used for IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus research[1].
BMS-986202 inhibits IFNα and IL-23 in Kit225 T cells with IC50 values of 10 nM and 12 nM, respectively[1].BMS-986202 is potent in the IFNα stimulated STAT5 phosphorylation human whole blood (hWB) assay and mouse whole blood (mWB) with IC50 values of 58 nM and 481 nM, respectively[1].
BMS-986202 (Compound 7; 3-30 mg/kg; p.o.; daily; for 9 days) treatment inhibits IL-23-driven acanthosis in mice[1].BMS-986202 (Compound 7; 0.4-10 mg/kg; p.o.) treatment inhibits IL-12/IL-18-induced IFNγ production in mice. BMS-986202 dose-dependently inhibits IFNγ production by 46% and 80% at doses of 2 mg/kg and 10 mg/kg, respectively[1].BMS-986202 (Compound 7; 7-10 mg/kg; p.o.) is stable in liver microsomes, with half lives of greater than 120 min in mouse, rat, monkey, and humans and 89 min in dog. The serum protein binding for BMS-986202 in these species ranges from 89.3% to 96.0%, leaving a good range of free fraction of drug available. BMS-986202 shows the oral bioavailability up to 62-100%[1].
[1]. Chunjian Liu, et al. Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2. J Med Chem. 2021 Jan 14;64(1):677-694.
| Cas No. | 1771691-34-9 | SDF | |
| 分子式 | C22H18D3FN6O3 | 分子量 | 439.46 |
| 溶解度 | DMSO : 250 mg/mL (568.88 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 | 2.2755 mL | 11.3776 mL | 22.7552 mL |
| 5 mM | 0.4551 mL | 2.2755 mL | 4.551 mL |
| 10 mM | 0.2276 mL | 1.1378 mL | 2.2755 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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。
Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2
J Med Chem 2021 Jan 14;64(1):677-694.PMID:33370104DOI:10.1021/acs.jmedchem.0c01698.
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
Identification of compounds acting as negative allosteric modulators of the LPA1 receptor
Eur J Pharmacol 2018 Aug 15;833:8-15.PMID:29807028DOI:10.1016/j.ejphar.2018.05.040.
The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4-({(Cyclopropylmethyl)[4-(2-fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK-615) with BMS-986202 and SAR-100842. Back-scattering interferometry (BSI) was used to show that the apparent affinity of TAK-615 was enhanced in the presence of LPA. The binding signal for BMS-986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR-100842 was also enhanced in the presence of LPA. Only BMS-986202 was able to fully inhibit the response to LPA in calcium mobilisation, β-arrestin, cAMP, GTPγS and RhoA functional assays. TAK-615 and SAR-100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK-615 is not competitive with either SAR-100842 or BMS-986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK-615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR-100842 also behaves like a NAM. BMS-986202 on the other hand behaves like an orthosteric antagonist.