CRF1 receptor

克里奈色芬（Crinecerfont）通过选择性拮抗促肾上腺皮质激素释放因子（CRF）1型受体发挥治疗作用。该受体在垂体中含量丰富。药物通过阻断CRF与垂体中CRF1型受体的结合，抑制垂体分泌促肾上腺皮质激素（ACTH）。ACTH的减少可导致肾上腺雄激素合成下降，从而降低17α-羟孕酮（17OH-progesterone）等类固醇前体物质的水平。

在8名接受推荐剂量克里奈色芬治疗两周的成年先天性肾上腺皮质增生症患者中，促肾上腺皮质激素（ACTH）水平较基线值的中位百分比降幅为62%。在针对成人和儿童经典CAH患者的三期临床试验中，在为期4周的初始糖皮质激素稳定期内使用推荐剂量的克里奈色芬，一项研究中ACTH水平降低了65%，另一项研究中降低了72%。需注意的是，接受克里奈色芬治疗的患者必须继续同时进行糖皮质激素替代治疗，且剂量应维持（或高于）皮质醇替代所需水平。任何剂量调整均应在医疗专业人员的监督下进行。

---

此前研究表明，选择性CRF₁受体拮抗剂SSR125543能够减轻创伤性应激暴露对小鼠产生的长期行为学和电生理学影响。睡眠障碍是创伤后应激障碍（PTSD）患者最常见症状之一。本研究旨在通过脑电图分析，在小鼠PTSD模型中探究SSR125543（腹腔注射10 mg/kg/天，持续2周）能否减轻创伤性应激暴露引起的睡眠/觉醒障碍。实验中，将SSR125543的效果与两种临床证实对PTSD有效的药物进行比较：5-羟色胺再摄取抑制剂帕罗西汀（腹腔注射10 mg/kg/天）和部分N-甲基-d-天冬氨酸受体激动剂D-环丝氨酸（腹腔注射10 mg/kg/天）。 实验流程包括：在施加两次1.5 mA足底电击前，先于家笼环境中进行6小时基线脑电图记录。从应激后第1天至第二次脑电图记录（应激后第14天进行）前一日持续给药。结果显示，应激后第14天，遭受电击的小鼠表现出睡眠碎片化，具体表现为非快速眼动睡眠和觉醒片段发生次数显著增加，但觉醒、非快速眼动睡眠和快速眼动睡眠的持续时间未受显著影响。SSR125543、帕罗西汀和D-环丝氨酸的反复给药均能预防上述应激诱导的效应。这些发现进一步证实，CRF₁受体拮抗剂SSR125543能够减轻创伤性应激暴露的有害影响[2]。

SSR125543 was suspended in saline with methylcellulose (0.6%) and Tween 80 (0.1%) to obtain concentrations of 1.0 mg/ml. The treatments began five hours after stress. Mice received one intraperitoneal (i.p.) administration per day of 10 ml/kg. The last administration was performed 30 min before the start of EEG recordings. The doses were validated in a previous study using the same procedure and the same species. It showed that 10 mg/kg represented the optimal dose to seek efficacy in this model [2].

Absorption
In adult patients at steady-state, the AUC0-24h and Cmax of crinecerfont were 72846 ng*h/mL and 4231 ng/mL, respectively. In pediatric patients at steady-state, the AUC0-24h ranged from 47062 to 74693 ng*h/mL and the Cmax ranged from 2887 to 4555 ng/mL, depending on the administered dose. The median time to Cmax (i.e. Tmax) is four hours.

Route of Elimination
Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% of the dose was recovered in feces (2.7% as unchanged parent drug) and 2% in urine (undetectable levels of unchanged parent drug).

Volume of Distribution
The mean apparent volume of distribution of crinecerfont in adults is 852 liters.

Clearance
The apparent clearance of crinecerfont is 3.5 L/h.

Protein Binding
Crinecerfont is highly (≥99.9%) protein bound in plasma.

Metabolism / Metabolites
_In vitro_, crinecerfont is primarily metabolized by CYP3A4 and to a lesser extent CYP2B6. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism.

Biological Half-Life
The effective half-life of crinecerfont is approximately 14 hours.

Hepatotoxicity
In registration clinical trials, liver test abnormalities were infrequent during crinecerfont therapy and no more common than with placebo. There were no instances of ALT or AST elevations above 3 times the upper limit of normal (ULN) and no cases of liver injury with jaundice or symptoms. Clinical experience with crinecerfont therapy has been limited, but there have no published reports of clinical apparent liver injury with its use. Likelihood score: E (unlikely cause of clinically apparent liver injury).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of crinecerfont during breastfeeding. Because crinecerfont is more than 99% bound to plasma proteins, amounts in milk are likely to be low. If a mother requires crinecerfont, it is not a reason to discontinue breastfeeding. Breastfed infants should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. https://pubchem.ncbi.nlm.nih.gov/compound/5282340
[2]. The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine. Behav Brain Res. 2015 Feb 15;279:41-6.

SSR 125543 is an amine.

---

Drug Indication
Treatment of atypical haemolytic uremic syndrome, Treatment of paroxysmal nocturnal haemoglobinuria
Treatment of congenital adrenal hyperplasia

Drug Indication
Crinecerfont is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients ≥4 years of age with classic congenital adrenal hyperplasia (CAH).

Treatment of atypical haemolytic uremic syndrome, Treatment of paroxysmal nocturnal haemoglobinuria

LiverTox Summary
Crinecerfont is small molecule inhibitor of the corticotropin releasing factor receptor which is used to treat patients with congenital adrenal hyperplasia. Crinecerfont is has not been associated with significant elevations in serum aminotransferase levels during therapy or with instances of clinically apparent liver injury.

---

Patients with congenital adrenal hyperplasia (CAH) face two major problems: adrenal insufficiency, caused by insufficient endogenous cortisol production, and androgen excess, caused by a counter-regulatory overproduction of adrenocorticotropic hormone (ACTH) from the pituitary. Standard therapy involves cortisol replacement, but typically requires supraphysiological glucocorticoid doses to lower both ACTH and adrenal androgens, resulting in chronic glucocorticoid overexposure. The majority of the poor health outcomes in patients with CAH result from the inability to precisely titrate glucocorticoid dosages to both adequately replace the deficiency and sufficiently attenuate excessive androgen production. Crinecerfont is a selective antagonist of corticotropin-releasing factor (CRF) type 1 receptor that works to reduce excessive ACTH secretion from the pituitary. When administered alongside glucocorticoid replacement in patients with CAH it allows for the use of lower, physiological doses for glucocorticoid replacement, thereby reducing the risks associated with glucocorticoid overexposure. Crinecerfont was approved by the FDA in December 2024 as an adjunct to glucocorticoid replacement in patients with CAH.
Crinecerfont is a Corticotropin-releasing Factor Type 1 Receptor Antagonist. The mechanism of action of crinecerfont is as a Corticotropin-releasing Factor Type 1 Receptor Antagonist.
Crinecerfont is small molecule inhibitor of the corticotropin releasing factor receptor which is used to treat patients with congenital adrenal hyperplasia. Crinecerfont is has not been associated with significant elevations in serum aminotransferase levels during therapy or with instances of clinically apparent liver injury.
CRINECERFONT is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for congenital adrenal hyperplasia and has 1 investigational indication.

C27H28CLFN2OS

483.04042

482.159

C, 67.14; H, 5.84; Cl, 7.34; F, 3.93; N, 5.80; O, 3.31; S, 6.64

752253-39-7

Crinecerfont hydrochloride;321839-75-2

5282340

Light yellow to yellow solid at room temperature

7.517

53.6

0

5

8

33

699

1

ClC1C=C(OC)C(C)=CC=1C1=C(C)SC(N(C(C2C=CC(C)=C(F)C=2)CC2CC2)CC#C)=N1

IEAKXXNRGSLYTQ-DEOSSOPVSA-N

InChI=1S/C27H28ClFN2OS/c1-6-11-31(24(13-19-8-9-19)20-10-7-16(2)23(29)14-20)27-30-26(18(4)33-27)21-12-17(3)25(32-5)15-22(21)28/h1,7,10,12,14-15,19,24H,8-9,11,13H2,2-5H3/t24-/m0/s1

(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine

SSR125543; SSR-125543; SSR 125543; Crinecerfont; 752253-39-7; SSR 125,543; SSR-125,543; Crenessity; SSR125,543A; SSR-125543A; SSR 125543A; Crinecerfont

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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。

---

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。

View More

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)

---

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。

View More

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

---

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。

---

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。