Mavacamten 对心肌肌球蛋白具有 >4 倍的选择性，在牛系统中的 IC50 值为 490 nM，在人类系统中为 711 nM，在兔系统中为 2140 nM[1]。

Mavacamten 治疗将 FS 从 52±3% 降低至 38±7%。 Mavacamten 治疗将 FS 从 81±7% 降低至 60±13%，相对降低了 25%。在所有检测中，FS 和 Mavacamten 血浆浓度之间存在线性关系； Mavacamten 浓度每增加 100 ng/mL，FS 就会降低 4.9%[2]。通过降低心肌肌球蛋白重链的腺苷三磷酸酶活性，mavacamten 降低收缩力。在肌球蛋白重链存在杂合人类突变的小鼠中，长期 Mavacamten 治疗可抑制心室肥大、心肌细胞紊乱和心肌纤维化的发展，并减弱肥厚和促纤维化基因的表达[3]。

稳态特性[1]
使用利用丙酮酸激酶和乳酸脱氢酶的偶联酶系统进行ATP酶测量。除非另有说明，否则在所有实验中使用的缓冲系统是在pH 6.8下的12mm管道、2mm MgCl2、1mm DTT（PM12缓冲液）。所有稳态实验均在20°C下使用SpectraMax 384Plus平板读取器进行，并使用SoftMax Pro软件包记录速率。对于所有稳态实验，数据一式三份收集并取平均值，n=3。n的值是指所执行的单个实验的数量。稳态系统的所有数据分析均使用GraphPad Prism进行

---

瞬态动力学特性[1]
使用停流装置（Hi-Tech Scientific，SF-61 DX2）进行瞬态动力学实验，以确定马瓦卡坦对肌球蛋白结合和从肌动蛋白丝解离、磷酸盐（Pi）释放以及肌球蛋白释放2′-（or-3′）-O-（N-甲基蒽酰基）-ADP（mant ADP/ATP）的影响。对于每个数据点，收集一式三份的瞬态痕迹，并对每个实验取平均值，n=3。所有瞬态实验都是用不同量的马伐卡坦或单一浓度的马伐卡坦在不同底物浓度下进行的，以确定每个动力学参数的浓度依赖性变化，对照实验是用2%DMSO终产物进行的。对于mant-ATP或mant-ADP实验，通过在365nm激发的400nm截止滤光片测量荧光发射。如前所述监测肌球蛋白结合mant-ATP后荧光的增加或释放mant-ADP后荧光的减少。[1]
使用根据Brune等人制备的7-二乙基氨基-3-[[[2-（马来酰亚胺基）乙基]氨基]羰基]香豆素（MDCC）染料修饰的细菌磷酸盐结合蛋白（PBP）来测量Pi的释放速率。以双混合模式设置停流仪器。在这种配置中，将不含核苷酸的肌球蛋白S1与ATP以1:1摩尔比混合，并老化2s以允许完全水解。然后将肌球蛋白核苷酸复合物与肌动蛋白加MDCC-PBP快速混合，并通过455nm截止滤光片在425nm激发下测量由于磷酸盐结合引起的荧光增加。该系统用于通过改变所有注射器中化合物的浓度并将数据与DMSO对照进行比较来测量马伐卡坦的效果。在数据收集之前，通过用“Pi-mop”浸泡从系统中去除污染磷酸盐，该“Pi-mob”由嘌呤核苷磷酸化酶和7-甲基鸟苷组成，浓度分别为1单位/ml和0.5 mm。该Pi-mop也以0.1单位/ml嘌呤核苷磷酸化酶和0.25mm 7-甲基鸟苷的浓度存在于所有溶液中，以去除任何残留的磷酸盐。[1]
通过S1与芘肌动蛋白结合时发生的芘荧光的猝灭来监测肌球蛋白S1与芘-肌动蛋白丝的结合。ATP诱导的acto-S1解离的动力学是通过监测芘与S1混合时芘荧光的增加与ATP浓度的增加来测量的。使用400nm截止滤光片在360nm激发下测量芘荧光。这种相互作用也用于监测肌球蛋白从弱结合状态到强结合状态到肌动蛋白的转变。简言之，将牛心肌肌球蛋白S1和ATP在单一周转条件下混合，并使其老化2秒以将ATP水解为ADP-Pi。然后将该混合物与芘肌动蛋白以1:1的比例与肌球蛋白和1mm ADP混合，以将平衡转变为强结合状态。用不同浓度的mavacamten监测芘肌动蛋白的猝灭，并分析反应幅度。[1]

如前所述制备心肌纤维。采集牛心脏组织，立即放在湿冰上，运输过夜，解剖左心室和隔膜，在液氮中冷冻，并在−80°C下储存。从BioReclamations IVT获取人体组织，并在收到当天制备肌原纤维。使用分别从牛左心室和兔腰大肌制备的全长肌球蛋白的糜蛋白酶消化制备心脏和骨骼肌球蛋白S1。根据Margossian和Lowey的方法制备牛心脏HMM。使用腺病毒感染方法在分化的小鼠C2C12肌管中表达人心肌肌球蛋白亚片段-1。重组产物利用必需轻链上的6×-组氨酸标签在Ni2+树脂上进行初步纯化，并通过阴离子交换和尺寸排阻色谱进行进一步纯化。将所有肌原纤维和肌球蛋白S1制剂置于10%蔗糖中，在液氮中快速冷冻，并在−80°C下储存。肌动蛋白由牛心脏丙酮粉末（Pel-Freez Biologicals）根据Spudich和Watt的方法制备。根据Criddle等人的方法制备芘肌动蛋白。[1]

Absorption, Distribution and Excretion
Mavacamten has an estimated oral bioavailability of at least 85% and Tmax of 1 hour. Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown.
Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged).
Through the use of a simple 4-species (mouse, rat, dog, and cynomolgus monkey) allometric scaling of unbound blood steady-state volume of distribution, the human volume of distribution of mavacamten is predicted to be 9.5 L/kg.
Mavacamten demonstrates a long terminal half-life and thus low clearance, with an estimated plasma clearance using human hepatocytes of less than 4.9 mL/min/kg. Assuming a one-compartment model, using simple allometric scaling of unbound blood clearance of mouse, rat, dog, and cynomolgus monkey, human plasma clearance of mavacamten is estimated to be 0.51 mL/min/kg.

---

Metabolism / Metabolites
Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).

---

Biological Half-Life
Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten's terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days.

Protein Binding
Plasma protein binding of mavacamten is between 97 and 98%.

[1]. A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. J Biol Chem. 2017 Oct 6;292(40):16571-16577.

[2]. A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy. PLoS One. 2016 Dec 14;11(12):e0168407.

[3]. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016 Feb 5;351(6273):617-21.

Mavacamten is a myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM). It received initial US FDA approval in 2022, and it is one of the first myosin inhibitors to be used in humans. Mavacamten was also approved by Health Canada in October 2022 and by EMA in July 2023 for the same indication.
Mavacamten is a Cardiac Myosin Inhibitor. The mechanism of action of mavacamten is as a Cardiac Myosin Inhibitor.

---

Drug Indication
Mavacamten is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms by the FDA, Health Canada, and the EMA.
Treatment of symptomatic obstructive hypertrophic cardiomyopathy.
Treatment of hypertrophic cardiomyopathy

---

Mechanism of Action
Myosin is a family of enzymes that can produce mechanical output by an ATP-mediated cyclic interaction with actin. When ATP is bound to the myosin head, it is hydrolyzed into ADP and organophosphate by myosin ATPase activity, and the energy produced from the reaction is stored in the myosin head. As the organophosphate dissociates from myosin, it shifts myosin into a strong binding state to actin, thus creating a myosin-actin complex otherwise known as "cross-bridging".Dissociation of the organophosphate also causes a conformation change in myosin that creates strain in the actin-myosin bridge that can only be released once the actin and myosin filaments slide past each other, thus shortening the sarcomere and create a muscle contraction. Once the sliding is completed, ADP is released to create further movement of the myosin head. Although this ADP release-induced movement is minor and unlikely to contribute to the sarcomere movement, researchers have hypothesized that this movement is likely essential in limiting the sliding velocity of actin.Finally, myosin then bind to a new ATP molecule to initiate the chemomechanical cycle again. Mavacamten reduces sarcomere hypercontractility by acting as an allosteric and reversible modulator of the beta-cardiac isoform of myosin to reduce its ATPase activity, thus reducing actin-myosin cross bridging. Specifically, mavacamten inhibits the phosphate release, the cycle's rate-limiting step, without affecting the ADP release rate in actin-bound myosin.Also, mavacamten inhibits binding of ADP-bound myosin to actin as well as ADP release to prime the myosin head to initiate turnover.Recently, it was also discovered when myosin is not in its active state to interact with actin, it exists in equilibrium between 2 energy sparing states: a disordered relaxed state, where interaction between actin and myosin by the thin filament regulatory proteins, and a super relaxed state, where significant myosin head-to-head interaction lengthen ATP turnover rate.. Mavacamten's binding to myosin can shift the equilibrium toward the super relaxed state, effectively exerting both a basal and actin-activated ATP inhibition.

C15H19N3O2

273.336

273.147

C, 65.91; H, 7.01; N, 15.37; O, 11.71

1642288-47-8

Mavacamten-d6;2453251-18-6;Mavacamten-d1;2453251-02-8;Mavacamten-d5;2453251-00-6

117761397

White to off-white solid powder

1.2±0.1 g/cm3

1.591

2.65

61.4Ų

2

3

4

20

411

1

O=C1NC(=CC(N1C(C)C)=O)N[C@@H](C)C1C=CC=CC=1

RLCLASQCAPXVLM-NSHDSACASA-N

InChI=1S/C15H19N3O2/c1-10(2)18-14(19)9-13(17-15(18)20)16-11(3)12-7-5-4-6-8-12/h4-11,16H,1-3H3,(H,17,20)/t11-/m0/s1

(S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione

MYK 461; SAR-439152; MYK-461; SAR 439152; SAR439152; Camzyos; MYK-461; SAR-439152; 6-[[(1S)-1-phenylethyl]amino]-3-propan-2-yl-1H-pyrimidine-2,4-dione; Mavacamten [INN]; Mavacamten [USAN]; MYK461; Mavacamten

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)

DMSO : ~83.33 mg/mL (~304.87 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.15 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。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (7.61 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 储备液加入到 900 μL 玉米油中并混合均匀。

---

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。