TM38837

CB1/cannabinoid receptor 1 (IC50 = 0.4 nM)

随后发现TM38837对总共112个次要药理学靶标（包括GPR55和GPR119）是干净的（在1µM下抑制率<30%），对CYP和其他代谢酶没有显著影响。该化合物已经过广泛的药理学和毒理学研究，将在单独的出版物中详细介绍[1]。TM38837具有相当低的亲脂性和5.2的较高LLE。在表1中，TM38837和另一种四唑TM40783的相关体外数据均具有手性α-甲基，与相应的未取代的苄酰胺相比，通常会提高CB1的效力、溶解度和代谢稳定性[1]。

由相应的4-氰甲基吡唑制备了几个系列不同的吡唑-3-甲酰胺，4-甲基羧酸和4-甲基四唑官能化的吡唑-3甲酰胺，并作为大麻素受体1（CB1）拮抗剂和反向激动剂进行了研究，目的是制备与利莫那班相比具有较少CNS（中枢神经系统）介导副作用的化合物。在饮食诱导的小鼠模型中，对化合物的亲脂性、溶解度、CB1效力、代谢、脑和肝的分布以及对体重减轻的影响进行了评估和优化。一些羧酸和四唑被选为特别有前景的药物，四唑TM-38837随后在各种肥胖动物模型中表现出令人印象深刻的疗效，在明显产生可忽略不计的脑暴露的剂量下，体重显著减轻，炎症和葡萄糖稳态的血浆标志物得到改善。TM38837成为第一个进入临床试验的外周限制性CB1拮抗剂或反向激动剂，支持其缺乏中枢神经系统作用，现在认为非中枢神经系统介导的疗效与高肝脏暴露有关。这为在非酒精性脂肪肝（NAFLD）和脂肪性肝炎（NASH）等其他适应症中探索开辟了机会。请注意，这是首次公开TM-38837的结构，文献中出现的其他结构与此程序无关。[1]

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尽管PK曲线良好，但这些酸的体内疗效较差或有限，而一些四唑（如TM-38837和TM40783）诱导了极好的体重减轻（分别为11.4%和11.8%），与利莫那班（14.5%）的效果相似，如图2所示。
小鼠Mini-DIO模型产生了可重复的效果，4项口服10mg/kg TM-38837的研究表明，与赋形剂治疗相比，体重减轻了11.4%、9.7%、10.1%和11.9%。四唑TM40783、TM38837在脑中的浓度较低，相当于血浆浓度的1%。与另一种酸相比，酸TM39875显示出更高的脑浓度，这可以解释前者观察到的6.4%的体重减轻，而后者为0.2%（图3）[1]。

The PK profiles were investigated for the best carboxylic acids and tetrazoles exemplified with the tetrazole TM38837 and the acid TM39875 (Table 3). Plasma protein binding (PPB) for both compounds were above 99 % in mouse plasma in accordance with other acidic compounds. We noted no P-glycoprotein (Pgp) transport for either compound in the Caco-2 model (efflux ratios were between 1.0 and 1.3 with or without the Pgp antagonist cyclosporin A). In mouse both compounds had very good oral bioavailability and low clearance but low volumes of distribution consistent with the high PPB. TM39875 and TM38837 consistently had measured brain levels of approximately 1 % of the plasma concentration without correction for blood contamination of brain tissue samples.[1]

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We observed a marked difference in the tissue distribution between the carboxylic acids and the tetrazoles (Table 4). Thus, a high liver concentration was confirmed for TM38837 and TM40783 in a separate PK study in obese mice with plasma and tissue measurements made 6 h after a single 10 mg/kg dose in contrast to TM39875. The adipose tissue levels of the carboxylic acids were 4 % of the plasma concentrations while the tetrazoles displayed 5- to 7-fold higher levels. All compounds had very low or undetectable brain levels at both the 6- and 24-hour timepoints. The overwhelming distribution to liver compared to other tissues and blood was also confirmed in a quantitative whole body autoradiography study in lean C57BL/6J mouse after dosing with [3H]-TM38837, while radioactivity in brain was close to the detection limit at all time points. This indicates that the effects seen on food intake and weight loss, induced by the tetrazoles, are likely driven to a large extent by inhibition of CB1 in the liver. Cf. additional data in Supplementary material. [1]

[1].Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837. Bioorg Med Chem Lett. 2023 Dec 1;98:129572.

Since the withdrawal of rimonabant there has been considerable interest in the metabolic effects of CB1 in peripheral organs and many groups have reported efficacy from peripherally restricted compounds. Typically the design of peripherally restricted compounds focuses upon low permeability, usually through increased PSA, and efflux mechanisms. However, such approaches can have detrimental effects on PK, particularly with regard to oral absorption, and there is inevitably a trade-off between effective exclusion of the compound from the CNS and a drug-like profile. The approach described herein was to incorporate different polar functionality onto the rimonabant template to reduce logD and improve physicochemical properties, whilst retaining potency and selectivity, then optimize mouse PK profiles and select compounds with high in vivo plasma/brain ratios for evaluation in PD studies. This approach identified acidic compounds with good bioavailability that were effectively restricted to the periphery but with sustained plasma exposure. Evaluation of selected acidic compounds in sub-chronic Mini-DIO studies led to identification of the tetrazole TM38837 which consistently produced weight loss of similar magnitude to rimonabant and subsequently became the first peripherally restricted CB1 inhibitor to enter clinical trials. In this double-blind, randomized, placebo-controlled, crossover study, healthy subjects received 5 × 4 mg tetrahydrocannabinol (THC) and TM38837, rimonabant or placebo. Supporting the present mouse studies TM38837 at 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. Weight-reducing efficacy of TM38837 and related analogues was associated with high liver levels which implicates hepatic CB1 upregulation as a driver of the obese phenotype. The peripheral profile of this type of CB1 antagonists with a high liver exposure opens possibilities for exploration of other indications such as nonalcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), liver fibrosis and type 2 diabetes.16 Notably, global knockout of the cannabinoid receptor 1 gene reduced the expression of the lipid droplet binding protein PLIN2 to alleviate hepatic steatosis.[1]

1034264-77-1

Typically exists as solid at room temperature

TM38837; 1253641-65-4; TM-38837; 1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-5-[5-[2-[4-(trifluoromethyl)phenyl]ethynyl]thiophen-2-yl]pyrazole-3-carboxamide; TM388371253641-65-4; CHEMBL3341897; VQOCBFYUDSBDCZ-UHFFFAOYSA-N; YD7836VJ3G;

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)

Typically soluble in DMSO (e.g. 10 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。