348.37

化学式

C21H17FN2O2

CAS号

851723-84-7, 950688-14-9 (sodium salt)

稳定性

3 years -20°C powder

2 years -80°C in solvent

4 mg/mL (11.48 mM)

Water

<1 mg/mL 难溶或者不溶

Ethanol

<1 mg/mL 难溶或者不溶

OC000459是一种有效的，选择性的D prostanoid receptor 2 (DP2)（前列腺素受体D2）拮抗剂，IC50为13 nM。

靶点

体外研究

OC000459抑制[3H]PGD2与来自转染人DP2的CHO细胞中细胞膜的结合，Ki为13 nM。OC000459也会从人Th2淋巴细胞的细胞膜取代[3H]PGD2，Ki为4 nM。OC000459剂量依赖性拮抗PGD2介导的钙离子动员，在表达DP2的完整CHO细胞中，IC50为28 nM。OC000459抑制人Th2细胞响应PGD2 (10 nM)的趋药性，IC50为28 nM。在离体白血球制备和肝素化人全血中，OC000459 (< 3 μM) 竞争性拮抗PGD2的作用。OC000459抑制嗜酸性红细胞响应DK-PGD2而形变，IC50为11 nM。OC000459 (1 μM)抑制Th2细胞的活化和噬酸细胞对肥大细胞上清液的响应。

体内研究

OC000459以2 mg/kg的剂量口服给药，在Sprague-Dawley大鼠体内表现出的血浆半衰期为2.9小时，达到最大血浆浓度的时间为1.3小时，最大血浆浓度为1.54 μg/mL。DK-PGD2注射前0.5小时，OC000459口服给药导致血浆嗜酸性粒细胞增多剂量依赖性减少，在大鼠体内ED50为0.04 mg/kg。DK-PGD2注射前0.5小时，OC000459口服给药也会剂量依赖性抑制嗜酸性细胞聚集，在大鼠体内，ED50为0.01 mg/kg。对全分析(FA)群体和每个方案(PP)群体的分析表明，OC000459 (200 mg，每天两次，给药28天)对中度持续性哮喘患者给药，能够改善生活质量。在这些患者中，OC000459提高夜间症状评分，减少痰嗜酸粒细胞的几何平均计数和呼吸道感染。在固醇类先天性哮喘患者中，OC000459 (200 mg，每天两次)治疗抑制后期哮喘反应和痰嗜酸粒细胞中过敏原增加。

Oclacitinib is a novel JAK inhibitor. Oclacitinib is most potent at inhibiting JAK1 (IC50=10 nM).

IC50 & Target

In Vitro

Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of Oclacitinib is determined against JAK family members and cytokines that trigger JAK activation in cells. Inhibitory activity of Oclacitinib against JAK family members is determined in isolated enzyme systems. Oclacitinib inhibits JAK1, JAK2, JAK3, and TYK2 by 50% at concentrations (IC50’s) of 10, 18, 99, and 84 nM, respectively. Oclacitinib is most potent against the JAK1 enzyme, showing a 1.8-fold selectivity for JAK1 vs. JAK2 and 9.9-fold selectivity toward JAK1 vs. JAK3. Oclacitinib inhibits JAK family members by 50% at concentrations (IC50’s) ranging from 10 to 99 nM and does not inhibit a panel of 38 non-JAK kinases (IC50’s > 1000 nM). Oclacitinib also inhibits the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50’s ranging from 36 to 249 nM. Oclacitinib has minimal effects on cytokines that does not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50’s > 1000 nM) .Topical treatment with Tofacitinib (0.1%) and Oclacitinib (0.1%) leads to significant reduction of cell migration from mouse ear explants compared with vehicle-treated ears (all P < 0.05). The cell counts of MHC class II positive cells (that is, Langerhans cells) are significantly lower in vehicle-treated compared with each JAK inhibitor–treated epidermis (all P < 0.01) .

In Vivo

Scratching bouts at the high dose in the Oclacitinib group are significantly less than in the vehicle-only group (P<0.01). Client-owned dogs (n=436) with moderate to severe owner-assessed pruritus and a presumptive diagnosis of allergic dermatitis are enrolled. Dogs are randomized to either Oclacitinib at 0.4-0.6 mg/kg orally twice daily or an excipient-matched placebo. An enhanced 10 cm visual analog scale (VAS) is used to assess the severity of pruritus from day 0 to 7 and to assess the severity of dermatitis on days 0 and 7. Dogs can remain on the study for 28 days. Oclacitinib produces a rapid onset of efficacy within 24 h.

Peficitinib

MB2615

Upadacitinib(ABT-494)

MB3924

AZD1480

1 mg

5 mg

10 mg

1 mM

2.9635 mL

14.8174 mL

29.6349 mL

5 mM

0.5927 mL

2.9635 mL

5.9270 mL

10 mM

0.2963 mL

1.4817 mL

2.9635 mL