Omarigliptin   中文名称: 奥格列汀

DPP-4 (IC50 = 1.6 nM)

体外活性：Omarigliptin（以前称为 MK-3102）是一种有效的、选择性的、长效的 DPP-4（二肽基肽酶 4）抑制剂，IC50 为 1.6 nM。它对所有测试的蛋白酶具有高度选择性 (IC50 > 67 μM)。它具有弱离子通道活性（IKr、Caγ1.2 和 Naγ1.5 时 IC50 > 30 μmol/L）。此外，在广泛的选择性反筛选（168 次放射性配体结合或酶测定）中的所有测定中均获得了 IC50 > 10 μmol/L。奥格列汀快速、竞争性地结合 DPP-4 的活性位点，这一过程是可逆的、高度选择性的，从而导致高血糖条件下胰岛素水平升高和胰高血糖素水平降低。它具有出色的药代动力学特征，适合每周一次给药，目前正在进行 3 期临床试验。激酶测定：奥马格列汀是 DPP-4 的有效抑制剂，比其他测试的蛋白酶具有高选择性 (IC50 > 67 μmol/L)，并且具有弱离子通道活性 (IKr、Caγ1.2 和 Naγ1 时 IC50 > 30 μmol/L) .5).此外，在广泛的选择性反筛选（168 次放射性配体结合或酶测定）中的所有测定中均获得了 IC50 > 10 μmol/L。奥格列汀快速、竞争性地结合 DPP-4 的活性位点，这一过程是可逆的、高度选择性的，从而导致高血糖条件下胰岛素水平升高和胰高血糖素水平降低。细胞测定：

在瘦小鼠中，在口服葡萄糖耐量试验 (OGTT) 中葡萄糖激发前 1 小时口服给药时，它以剂量依赖性方式显着降低血糖波动，从 0.01 mg/kg（葡萄糖 AUC 降低 7%）至 0.3毫克/千克（减少 51%）。奥格列汀的给药剂量依赖性地增加活性 GLP-1 的血浆浓度。奥格列汀在雄性 Sprague-Dawley 大鼠和比格犬中的药代动力学特征为低血浆清除率 (0.9−1.1 mL/min/kg)、稳态分布容积为 0.8−1.3 L/kg 和长末端半衰期（∼11−22 h）。奥格列汀在狗和大鼠中的口服生物利用度均良好（约 100%）。奥格列汀在研究期间具有良好的耐受性，未发现死亡或体征。

Omarigliptin 是一种有效的 DPP-4 抑制剂，具有弱离子通道活性（IC50 > 30 μmol/L，IKr、Caγ1.2 和 Naγ1.5），并且比其他测试的蛋白酶具有强选择性（IC50 > 67 μmol/L）。此外，在包含 168 项放射性配体结合或酶测定的广泛选择性反筛选中的每次测定中，均实现了 IC50 > 10 μmol/L。在高血糖情况下，奥格列汀快速且竞争性地与 DPP-4 活性位点结合，这是一个可逆且高度选择性的过程，可提高胰岛素水平并降低胰高血糖素水平。

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体外药理学[1]
Omarigliptin是DPP-4的竞争性可逆抑制剂（IC50=1.6 nM，Ki=0.8 nM），比西格列汀更有效（IC50=18 nM）。它对所有测试的蛋白酶都具有高度的选择性（IC50>67μM），包括QPP、FAP、PEP、DPP8和DPP9。该化合物具有微弱的离子通道活性（在IKr、Cav1.2和Nav1.5下的IC50>30μM）。MDS Pharma进行了广泛的选择性反筛选（168次放射性配体结合或酶分析）。在所有检测中，IC50均大于10μM。

12 weeks, C57BL/6 male mice
2.5, 5 mg/kg
P.o.; once a week for 8 weeks (50 mg/kg streptozotocin (STZ); i.p.; daily for five days)

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In Vivo Pharmacology in Preclinical Species[1]
Omarigliptin was evaluated for its ability to improve glucose tolerance in lean mice. When orally administered 1 h prior to dextrose challenge in an oral glucose tolerance test (OGTT), it significantly reduced blood glucose excursion in a dose-dependent manner from 0.01 mg/kg (7% reduction in glucose AUC) to 0.3 mg/kg (51% reduction). The efficacy of glucose lowering in this model was similar to that achieved with sitagliptin. In the corresponding pharmacodynamic (PD) assay, omarigliptin-mediated plasma DPP-4 inhibition and plasma compound concentrations were dose-dependent. At the 0.3 mg/kg dose (corresponding to maximum acute glucose lowering efficacy), plasma DPP-4 activity was inhibited by 85% (uncorrected for assay dilution), which exceeds the target inhibition (80%) associated with maximal glucose lowering efficacy. The observed plasma DPP-4 inhibition was consistent with the measured plasma inhibitor concentration (521 nM) and the potency of the compound against murine plasma DPP-4 (IC50 = 43.9 nM in 50% mouse plasma). In addition, the administration of omarigliptin dose-dependently increased plasma concentrations of active GLP-1 (GLP-1[7–36]amide and GLP-1[7–37]) in this study, with the maximal increase in active GLP-1 observed at the 0.3–1 mg/kg dosages. The augmentation of active GLP-1 levels achieved at these doses (>10-fold) was in the range of elevation in circulating hormone observed in DPP-4-deficient (Dpp4–/–) mice (3- to 8-fold) relative to wild type animals

Pharmacokinetics (PK) in Preclinical Species[1]
PK experiments were generally conducted as follows: All species were fasted overnight before dosing, provided water ad libitum, and fed 4 h following drug treatment. Blood was collected at predetermined intervals for all species into EDTA-containing tubes and centrifuged. Plasma was harvested and stored at −70 °C until analysis.

Test compounds were typically formulated as solutions in saline. Fasted male Sprague–Dawley rats were given either an iv dose of test compound solution via a cannula implanted in the femoral vein (n = 2) or a po dose by gavage (n = 3). Serial blood samples were collected at 5 (iv only), 15, and 30 min and at 1, 2, 4, 6, 8, 24, and 48 h postdose. Plasma was collected by centrifugation, and plasma concentrations of test compound were determined by LC–MS/MS following protein precipitation with acetonitrile.

Fasted dogs were administered intravenous doses via the cephalic vein (dogs, n = 2). Oral doses were administered via gastric gavage (n = 2). Serial blood samples were collected at 5 (iv only), 15, and 30 min and at 1, 2, 4, 6, 8, 24, 30, 48, and 72 h postdose. Plasma was collected by centrifugation, and plasma concentrations of test compound were determined by LC–MS/MS following protein precipitation with acetonitrile. Pharmacokinetic parameters were calculated by established noncompartmental methods.

The pharmacokinetics of omarigliptin in male Sprague–Dawley rat and beagle dog were characterized by a low plasma clearance (0.9–1.1 mL min–1 kg–1), a volume of distribution at steady state of 0.8–1.3 L/kg, and a long terminal half-life (∼11–22 h) (Table 1). The oral bioavailability of omarigliptin was good in both dogs and rats (∼100%). The mean percentage of unbound [3H]omarigliptin (1, 10, and 100 μM) in CD-1 mouse, Sprague–Dawley rat, beagle dog, and human plasma was 38%, 15%, 43%, and 68%, respectively. The blood-to-plasma concentration ratio in these species ranged from 0.6 to 1.2.

Omarigliptin has a long half-life (rat, 11 h; dog, 22 h) and lower clearance (rat, 1.1 mL min–1 kg–1; dog, 0.9 mL min–1 kg–1) in preclinical species. On the basis of the human PK prediction, omarigliptin is projected to be amenable for once-weekly dosing. This is recapitulated in the clinical studies, where omarigliptin is shown to have a biphasic PK profile with a terminal half-life of 120 h.

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Pharmaceutical Properties[1]
Omarigliptin used for clinical trial is a white material. Crystallinity was confirmed by optical microscopy and XRPD. Differential scanning calorimetry (DSC) showed a melting endotherm at 176.0 °C (heat of fusion, 89.68 J/g). The glass transition temperature of the amorphous material was found to be 58 °C. An anhydrous crystalline free base of omarigliptin is chemically and physically stable at 40 °C/75% RH for up to 4 weeks. Omarigliptin was shown to be photostable as a bulk material under 100 000 lx·h of cool white fluorescent light.[1]
After a 24 h equilibration in aqueous buffer, the concentration of omarigliptin is 7.1 mg/mL (pH 2), 8.7 mg/mL (pH 6), and 3.1 mg/mL (pH 8). After a 24 h equilibration of omarigliptin in buffer, the concentration of omarigliptin was >20 mg/mL (pH 2–6) and 6.2 mg/mL at pH 8. Omarigliptin has two pKa values measured at 3.5 and 7.1.

Omarigliptin is negative in the Ames mutagenicity assay.[1]
In the PatchXpress cardiac ion channel panel, omarigliptin exhibited minimal functional inhibition of hERG current up to the highest tested concentration of 30 μM. In the nonfunctional MK-499 displacement binding studies the compound had an IC50 of >30 μM, and there were no remarkable effects on IKs, INa, and ICaL up to 30 μM.[1]
Omarigliptin was also evaluated in an exploratory 14-day oral safety study in male rats at 100 mg kg–1 day–1. The compound was well tolerated over the duration of the study, with no mortality or physical signs noted. Clinical pathology findings were limited to slight decreases in glucose, triglycerides, and cholesterol. The AUC(0–24h), Cmax, and Tmax were 5003 μM·h, 371 μM, and 2 h, respectively.

[1]. J Med Chem . 2014 Apr 24;57(8):3205-12.

[2]. Drugs . 2015 Nov;75(16):1947-52.

Omarigliptin is a pyrrolopyrazole.
Omarigliptin has been used in trials studying the treatment of Type 2 Diabetes Mellitus and Chronic Renal Insufficiency.

C17H20F2N4O3S

398.43

398.122

C, 51.25; H, 5.06; F, 9.54; N, 14.06; O, 12.05; S, 8.05

1226781-44-7

46209133

White to off-white solid powder

1.6±0.1 g/cm3

529.4±60.0 °C at 760 mmHg

274.0±32.9 °C

0.0±1.4 mmHg at 25°C

1.689

0.46

98.83

1

8

3

27

649

3

S(C([H])([H])[H])(N1C([H])=C2C(C([H])([H])N(C2([H])[H])[C@@]2([H])C([H])([H])O[C@]([H])(C3C([H])=C(C([H])=C([H])C=3F)F)[C@]([H])(C2([H])[H])N([H])[H])=N1)(=O)=O

MKMPWKUAHLTIBJ-ISTRZQFTSA-N

InChI=1S/C17H20F2N4O3S/c1-27(24,25)23-7-10-6-22(8-16(10)21-23)12-5-15(20)17(26-9-12)13-4-11(18)2-3-14(13)19/h2-4,7,12,15,17H,5-6,8-9,20H2,1H3/t12-,15+,17-/m1/s1

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)oxan-3-amine

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.27 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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: ≥ 2.5 mg/mL (6.27 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 25.0 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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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.27 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。