BTK (IC50 = 3 nM)

体外活性：在原代人 CLL 细胞的体外信号传导测定中，acalabrutinib 抑制 ERK、IKB 和 AKT 下游靶标的酪氨酸磷酸化。 Acalabrutinib 对 BTK 具有更高的选择性，对 9 种具有与 BTK 相同位置的半胱氨酸残基的激酶进行 IC50 测定。重要的是，与依鲁替尼不同，acalabrutinib 不会抑制 EGFR、ITK 或 TEC。 acalabrutinib 对 EGFR 酪氨酸残基 Y1068 和 Y1173 磷酸化没有影响。与 ibrutinib 相比，acalabrutinib 对 ITK、EGFR、ERBB2、ERBB4、JAK3、BLK、FGR、FYN、HCK、LCK、LYN、SRC 和 YES1 激酶活性具有更高的 IC50（>1000 nM）或几乎没有抑制作用。激酶测定：先前的研究表明，当针对一组 395 个非突变激酶进行测试时，ACP-196 对 Btk 具有高选择性，这与 ACP-196 亲电子试剂的内在反应性降低有关。此外，ACP-196 不能抑制 EGFR、Itk 或 Txk，这与依鲁替尼不同。此外，对 EGFR 表达细胞系的磷流分析进一步证实了依鲁替尼对 EGFR 的抑制作用，而没有观察到 ACP-196 的抑制作用。细胞测定：对 EGFR 表达细胞系的磷流测定进一步证实了依鲁替尼对 EGFR 的抑制作用，而没有观察到 ACP-196 的抑制作用。

小鼠口服 ACP-196 会导致 CD19+ 脾细胞中抗 IgM 诱导的 CD86 表达受到剂量依赖性抑制，ED50 为 0.34 mg/kg，而依鲁替尼为 0.91 mg/kg。使用类似的模型来比较单次口服剂量 25 mg/kg 后 Btk 抑制的持续时间。 ACP-196 在给药后 3 小时抑制 CD86 表达 >90%。

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Acalabrutinib (ACP-196)的临床前研究[1]
Acalabrutinib/阿卡拉布替尼在几种B细胞非霍奇金淋巴瘤(NHL)动物模型中进行了评估。这些研究为阿卡拉布替尼进入人体试验提供了必要的临床前体内数据。在犬B细胞NHL模型研究中，12只B细胞NHL犬口服阿卡拉布替尼，剂量逐渐递增，每24小时2.5 mg/kg(6只狗)，每24小时5 mg/kg(5只狗)，或每12小时10 mg/kg(1只狗)。结果，3只狗获得部分缓解(PR)， 3只狗病情稳定(SD)，而其余6只狗病情进展(PD)。因此，本研究表明阿卡拉布替尼在自发性NHL大型动物模型中具有单药生物活性。[1]

阿卡拉布替尼对CLL细胞的体内作用在移植人CLL细胞的NSG小鼠模型中得到了证实。阿卡拉布替尼在所有剂量水平下均能显著抑制NSG小鼠脾脏中人CLL细胞的增殖，检测Ki67的表达(P = 0.002)。阿卡拉布替尼治疗后肿瘤负荷呈剂量依赖性下降。阿卡拉布替尼通过降低plc - γ - 2的磷酸化来抑制BCR信号传导。阿卡拉布替尼可瞬间增加外周血CLL细胞计数。因此，新型BTK抑制剂acalabrutinib对移植到NSG小鼠模型的人CLL细胞具有体内抑制作用。 < br > < br > 在另一项体内研究中使用了两只小鼠模型。在TCL1过继性转移模型中，阿卡拉布替尼通过降低BTK的自磷酸化和降低BCR激活标志物CD86和CD69的表面表达来抑制BCR信号传导。最有趣的是，阿卡拉布替尼治疗显著提高了小鼠的生存率(中位81天vs 59天，P = 0.02)。第二种小鼠模型为NSG异种移植模型。阿卡拉布替尼显著降低了plc - γ - 2和ERK的磷酸化水平(P = 0.02)，降低了肿瘤细胞的增殖(P = 0.02)，降低了肿瘤负荷(P = 0.04)。Acalabrutinib在两种小鼠CLL模型中均显示为BTK的有效抑制剂。

根据之前的一项研究，当针对一组 395 个非突变激酶进行测试时，ACP-196 的亲电子试剂固有反应性降低与其对 Btk 的高选择性有关。与依鲁替尼相反，ACP-196 无法抑制 EGFR、Itk 或 Txk。通过对表达 EGFR 的细胞系进行磷酸流分析，进一步证实了依鲁替尼在不抑制 ACP-196 的情况下抑制 EGFR 的作用。

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与ibrutinib和CC-292相比，ACP-196在竞争结合实验中对395种非突变激酶(1 μM)进行了分析，显示出更高的Btk选择性。对与Btk相同位置的9个激酶的IC50测定表明，ACP-196的选择性最强。选择性的提高与ACP-196亲电试剂的本征反应性降低有关。重要的是，与依鲁替尼不同，ACP-196不抑制EGFR、Itk或Txk。在表达EGFR的细胞株上进行的磷酸流实验证实了依鲁替尼对EGFR的抑制作用(EC50: 47 ~ 66 nM)，而在10 μM下对ACP-196没有抑制作用。这些数据可以解释依鲁替尼相关的腹泻和皮疹发生率。伊鲁替尼对Itk和Txk的效力可能解释了为什么它会干扰治疗性CD20抗体的细胞介导的抗肿瘤活性和肿瘤微环境中免疫介导的杀伤。 在人全血中，ACP-196和伊鲁替尼在低nM范围内对b细胞受体诱导的反应表现出强大的、同等的抑制活性，而CC-292的抑制作用弱10-20倍。[3]

磷酸流测试中使用的表达 EGFR 的细胞系进一步验证了依鲁替尼对 EGFR 的抑制作用，未观察到任何 ACP-196 抑制作用。

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最近认识到b细胞受体(BCR)信号是b细胞恶性肿瘤(包括非霍奇金淋巴瘤(NHL))进展的关键因素，导致许多靶向治疗方法的发展，抑制这一信号通路。Ibrutinib是一种布鲁顿酪氨酸激酶(Btk)的小分子抑制剂，Btk是BCR通路中的关键信号分子，已在广泛的b细胞癌中显示出显着的临床活性。ACP-196是第二代Btk抑制剂，与伊鲁替尼相比，具有更高的靶标选择性和更高的体内效价，因此可能比其前身有所改进。在接下来的研究中，我们试图评估ACP-196在犬b细胞NHL模型中的作用，最终目的是为ACP-196进入人体临床试验提供必要的临床前数据。利用两种免疫表型证实的犬b细胞淋巴瘤细胞系CLBL-1和17-71，我们证明了ACP-196在低至10nM的浓度下治疗1小时后，对Btk和下游效应物ERK 1/2和PLCγ2的激活有有效的体外抑制作用。[2]

canine model of B cell NHL
2.5, 5, 10 mg/kg.
orally administered

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In vivo studies were performed in companion dogs as part of an ongoing clinical trial. Twelve dogs with immunophenotypically confirmed, spontaneously occurring B-cell NHL were orally administered ACP-196 at dosages of 2.5mg/kg every 24 hours (6 dogs), 5mg/kg every 24 hours (5 dogs), or 10mg/kg every12 hours (1 dog). Btk occupancy in peripheral blood and lymphoma cells was assessed using a biotin-tagged probe derived from ACP-196. Using this assay we found that at 2.5mg/kg full Btk occupancy was achieved in peripheral B cells 3h after dosing for all dogs, except for a single dog with high peripheral B-cell count. At 24 hours after dosing, 83-99% Btk target occupancy was observed for all dogs. Partial response, as assessed by a modified RECIST scheme, was achieved in 2 dogs in the 2.5mg/kg group and the dog in the 10mg/kg group. Upon relapse, one of the responders in the 2.5mg/kg group was dose escalated to 10mg/kg q12 on day 42 and partial response from relapse was reestablished. Of the remaining 9 dogs, 3 achieved stable disease for > 28 days and 6 discontinued the study after developing progressive disease within 28 days of starting treatment. In total, to date, 3 dogs achieved a partial response, 3 dogs stable disease, and 6 dogs progressive disease. ACP-196 was well tolerated with only mild anorexia noted in some dogs. These data demonstrate that ACP-196 has single agent biologic activity in a spontaneous large animal model of human NHL. Studies in dogs with NHL are ongoing to define regimens prior to initiation of human phase I clinical trials. Additional cohorts are planned combining ACP-196 with a phosphatidylinositide 3-kinase (PI3K) delta-specific inhibitor.[2]

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In vivo, oral administration of ACP-196 in mice resulted in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model was used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 and ibrutinib inhibited CD86 expression >90% at 3h and ∼50% at 24h postdose. In contrast, CC-292 inhibited ∼50% at 3h and ∼20% at 24h postdose. An ELISA based Btk target occupancy assay was developed to measure target coverage in preclinical and clinical studies. In healthy volunteers, ACP-196 at an oral dose of 100 mg QD showed >90% target coverage over a 24h period. Btk occupancy and regulation of the PD markers (CD69 and CD86) correlated with PK parameters for exposure. In CLL patients, after 7 days of dosing with ACP-196 at 200 mg QD, 94% Btk target occupancy was observed compared with ∼80% reported for ibrutinib at 420 mg QD [3].

Absorption
The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours.

Route of Elimination
After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite.

Volume of Distribution
The mean steady-state volume of distribution is approximately 34 L.

Clearance
Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis.

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Metabolism / Metabolites
Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK.

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Biological Half-Life
After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours. The half-life of the active metabolite, ACP-5862, is about 6.9 hours.

Hepatotoxicity
In open label clinical trials of acalabrutinib in patients with CLL and mantle cell lymphoma, serum aminotransferase elevations occurred in 19% to 23% of patients during therapy and rose to above 5 times ULN in 2% to 3%. These elevations were transient and resolved spontaneously but occasionally led to early drug discontinuation. Among the 610 patients treated with acalabrutinib in pre-registration trials, there were no instances of clinically apparent liver injury attributed to its use, but there was a single instance of acute liver failure and death due to reactivation of hepatitis B. Similar cases of reactivation have been reported with ibrutinib, another small molecule inhibitor of Bruton's tyrosine kinase. Experience with acalabrutinib has been limited and the frequency of clinically apparent liver injury and reactivation of hepatitis B are not known. The majority of cases have occurred in patients taking multiple immunosuppressive agents and not just acalabrutinib alone.
Likelihood score: D (possible rare cause of reactivation of hepatitis B).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of acalabrutinib during breastfeeding. Because acalabrutinib is over 97% bound to plasma proteins, and the half-life of the drug and metabolite are less than 7 hours, the amount in milk is likely to be low. However, the protein binding of the active metabolite is not known and the manufacturer recommends that breastfeeding be discontinued during acalabrutinib therapy and for at least 2 weeks after the final dose.

◉ 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.

Drugs and Lactation Database

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Protein Binding
Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7. _In vitro_ experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein.

[1]. J Hematol Oncol . 2016 Mar 9:9:21.

[2].Cancer Res (2014) 74 (19_Supplement): 1744.

[3]. Cancer Res (2015) 75 (15_Supplement): 2596.

Acalabrutinib is a member of the class of imidazopyrazines that is imidazo[1,5-a]pyrazine substituted by 4-(pyridin-2-ylcarbamoyl)phenyl, (2S)-1-(but-2-ynoyl)pyrrolidin-2-yl, and amino groups at positions 1, 3 and 8, respectively. It is an irreversible second-generation Bruton's tyrosine kinase (BTK) inhibitor that is approved by the FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a secondary carboxamide, a member of benzamides, a member of pyridines, an aromatic amine, a pyrrolidinecarboxamide, an imidazopyrazine, a ynone and a tertiary carboxamide.

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To date, acalabrutinib has been used in trials studying the treatment of B-All, myelofibrosis, ovarian cancer, multiple myeloma, and Hodgkin lymphoma, among others. As of October 31, 2017 the FDA approved Astra Zeneca's orally administered Calquence (acalabrutinib, capsules). This Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and in adult patients with Mantle cell lymphoma (MCL) who have already received at least one prior therapy. In August 2022, the FDA approved a new tablet formulation of Calquence, enabling the co-administration of this drug with proton pump inhibitors (PPIs). Unlike Calquence capsules, the co-administration of Calquence tablets and PPIs does not have an effect in the pharmacokinetics of acalabrutinib. Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK. Nevertheless, acalabrutinib was approved under the FDA's accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib's currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials. Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib.

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Acalabrutinib is a Kinase Inhibitor. The mechanism of action of acalabrutinib is as a Tyrosine Kinase Inhibitor. Acalabrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of B cell malignancies including refractory mantle cell lymphoma and chronic lymphocytic leukemia. Acalabrutinib has been associated with mild-to-moderate serum enzyme elevations during therapy but has not been linked to instances of idiosyncratic acute liver injury, although it has been associated with cases of reactivation of hepatitis B which can be severe and even fatal.

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Acalabrutinib is an orally available inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, acalabrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

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Drug Indication
Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma.

Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.

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Pharmacodynamics
Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection.

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Mechanism of Action
Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects.

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More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib.[1]

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Recent recognition of B-cell receptor (BCR) signaling as a critical factor in the progression of B-cell malignancies, including non-Hodgkin lymphoma (NHL), has resulted in the development of numerous targeted therapeutics that inhibit this signaling pathway. Ibrutinib, a small molecule inhibitor of Bruton tyrosine kinase (Btk) a key signaling molecule in the BCR pathway, has demonstrated significant clinical activity in a broad range of B-cell cancers. ACP-196 is a second generation Btk inhibitor with increased target selectivity and enhanced in vivo potency compared with ibrutinib and, thus, may represent an improvement over its predecessor. With the following studies, we sought to evaluate ACP-196 in canine models of B-cell NHL with the ultimate goal of providing the preclinical data necessary to move ACP-196 into human clinical trials. Using two immunophenotypically confirmed canine B-cell lymphoma cell lines, CLBL-1 and 17-71, we demonstrate potent in vitro inhibition of activation of Btk and the downstream effectors ERK 1/2 and PLCγ2 following 1 hour of treatment with ACP-196 at concentrations as low as 10nM. [2]

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Ibrutinib, a first generation Btk inhibitor, is approved for the treatment of CLL and mantle cell lymphoma; known toxicities include atrial fibrillation, diarrhea, rash, arthralgia and bleeding events (1). Recent reports show ibrutinib's off target effects may negatively impact its potential for combined therapy with anti-CD20 antibodies (2,3). Here we describe the pharmacologic characterization of ACP-196 a potent, novel second generation Btk inhibitor, which binds covalently to Cys481 with improved selectivity and in vivo target coverage. Compared to ibrutinib and CC-292, ACP-196 demonstrated higher selectivity for Btk when profiled against a panel of 395 non-mutant kinases (1 μM) in a competitive binding assay. IC50 determinations on 9 kinases with a Cys in the same position as Btk showed ACP-196 to be the most selective. The improved selectivity is related to the reduced intrinsic reactivity of ACP-196's electrophile. Importantly, unlike ibrutinib, ACP-196 did not inhibit EGFR, Itk or Txk. Phosphoflow assays on EGFR expressing cell lines confirmed ibrutinib's EGFR inhibition (EC50: 47-66 nM) with no inhibition observed for ACP-196 at 10 μM. These data may explain the ibrutinib-related incidence of diarrhea and rash. Ibrutinib's potency on Itk and Txk may explain why it interferes with cell-mediated anti-tumor activities of therapeutic CD20 antibodies and immune-mediated killing in the tumor microenvironment (2,3). In human whole blood, ACP-196 and ibrutinib showed robust and equipotent inhibitory activity on B-cell receptor induced responses in the low nM range, whereas CC-292 was 10-20 fold less potent. In vivo, oral administration of ACP-196 in mice resulted in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model was used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 and ibrutinib inhibited CD86 expression >90% at 3h and ∼50% at 24h postdose. In contrast, CC-292 inhibited ∼50% at 3h and ∼20% at 24h postdose. An ELISA based Btk target occupancy assay was developed to measure target coverage in preclinical and clinical studies. In healthy volunteers, ACP-196 at an oral dose of 100 mg QD showed >90% target coverage over a 24h period. Btk occupancy and regulation of the PD markers (CD69 and CD86) correlated with PK parameters for exposure. In CLL patients, after 7 days of dosing with ACP-196 at 200 mg QD, 94% Btk target occupancy was observed compared with ∼80% reported for ibrutinib at 420 mg QD.[3]

C26H23N7O2

465.51

465.191

C, 67.08; H, 4.98; N, 21.06; O, 6.87

1420477-60-6

Acalabrutinib-d4;2699608-18-7;Acalabrutinib-d3; 1420477-60-6; 2058091-99-7 (citrate); 2242394-65-4; 2058091-96-4 (phosphate); 2058091-93-1 (3 hydrate); 2058092-05-8 (sulfate); 2058091-94-2 (fumarate); 2058091-97-5 (tartrate)

71226662

Yellow solid powder

1.4±0.1 g/cm3

1.715

0.77

118.51

O=C(C#CC([H])([H])[H])N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C1=NC(C2C([H])=C([H])C(C(N([H])C3=C([H])C([H])=C([H])C([H])=N3)=O)=C([H])C=2[H])=C2C(N([H])[H])=NC([H])=C([H])N12

WDENQIQQYWYTPO-IBGZPJMESA-N

InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1

4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide

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: ≥ 2.08 mg/mL (4.47 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 20.8 mg/mL澄清DMSO储备液加入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: ≥ 2.08 mg/mL (4.47 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 20.8 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: ≥ 2.08 mg/mL (4.47 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 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 2% DMSO+30% PEG 300+2% Tween 80+ddH2O: 6mg/mL

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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。