HIV-1

Temsavir/BMS-626529 的半最大有效浓度 (EC50) 值 <10 nm= 反对= 绝大多数= 大部分= 病毒= 分离株。= bms-626529= 表现= 平均= ec50= lai= 病毒= 0.4= nm.= 0.01= 最易受影响= 并且=>2,000 nM 针对最不易受影响的病毒。在来自不同人体组织的多种细胞类型中检查了 BMS-626529 的细胞毒性特征。在 MT-2（T 淋巴细胞）、HEK293（肾）、HEp-2（喉）、HepG2（肝）、HeLa（子宫颈）、HCT116（结直肠）、MCF-7（乳腺）中观察到 CC50 值 >200 μM 、SK-N-MC（神经上皮）、HOS（骨）、H292（肺）和 MDBK（牛肾）细胞在培养 3 或 6 天后进行测量。培养 6 天后，T 细胞系 PM1 和 PBMC 中的 CC50 值分别为 105 和 192 μM。这些结果表明，BMS-626529 在细胞培养物中表现出较低的细胞毒性[1]。 BMS-626529 对一组临床分离株表现出广谱抗病毒活性，50% 抑制浓度 (IC50) 范围从亚纳摩尔水平到 >0.1 µM[2]。

血浆HIV-1 RNA载量较基线的最大中位数下降范围为1.21至1.73 log(10)拷贝/mL。BMS-626529的血浆浓度与抗病毒反应无关，而低基线抑制浓度和最低和平均稳态BMS-626529血浆浓度，当通过基线蛋白结合调整的90%抑制浓度(抑制商)调整时，与抗病毒反应相关。BMS-663068总体耐受良好。 结论:联合或不联合利托那韦给药BMS-663068 8天可显著降低血浆HIV-1 RNA水平，并且通常耐受性良好。BMS-663068作为联合抗逆转录病毒治疗的一部分进行长期临床试验是有必要的。临床试验注册，nct01009814 .[2]

Micro BioSpin 6 柱用于测量 [3H]BMS-488043 或 [3H]BMS-626529 与 gp120 的结合。使含有 25 mM Tris-HCl (pH 7.5)、125 mM NaCl、50 nM gp120JRFL 和 [3H]BMS-488043 或 [3H]BMS-626529 连续稀释液的结合溶液 (30 μL) 平衡，然后吸附到MicroBioSpin 6 色谱柱。将柱离心（~14,000 rpm）5 分钟，收集洗脱液，并用闪烁计数器测定放射性。为了测量解离动力学，将 150 nM [3H]BMS-626529 或 90 nM [3H]BMS-488043 与 60 nM gp120 在环境温度下孵育 1 小时以实现平衡结合，然后大摩尔过量（14 倍）添加可溶性 CD4 蛋白以驱动解离。在指定的时间间隔取出等分试样，吸附到旋转柱上，然后离心，并对洗脱液中的放射性进行定量。通过比较经过和不经过可溶性 CD4 激发的平行样品的氚信号，可以确定化合物结合百分比[1]。

细胞毒性测定在连续稀释的 BMS-626529 存在下进行长达 6 天，并使用 XTT 测定对细胞活力进行定量。为了确定 CC50 值（杀死 50% 细胞所需的药物浓度），实验室适应的外周血单核细胞 (PBMC) 最初以 0.1×106 个细胞/mL 的密度进行铺板。在没有化合物的情况下，细胞密度通常在 6 天后达到 1×106 至 1.2×106/mL[1]。

Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068.[2]

Absorption
The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration. Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%. The Cmax and AUCtau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a Tmax of approximately 2 hours. Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%.

Route of Elimination
Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites. Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug.

Volume of Distribution
The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L.

Clearance
The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively.

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Metabolism / Metabolites
Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen. Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4. Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination. Both temsavir and its two predominant metabolites are known to inhibit BCRP.

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Biological Half-Life
The half-life of temsavir is approximately 11 hours. Fostemsavir is generally undetectable in plasma following oral administration.

Hepatotoxicity
In registration clinical trials, fostemsavir was associated with alanine aminotransferase (ALT) elevations in up to 25% of patients, but levels above 5 times the upper limit of normal (ULN) arose in only 4% of subjects. Most ALT elevations were transient, asymptomatic, and did not require dose modification or discontinuation. The more marked ALT elevations were usually attributable to other conditions or complications of HIV infection. No convincing cases of fostemsavir induced liver injury were observed in preregistration trials. Since approval of fostemsavir for use as a part of a multidrug therapy of HIV, there have been no published case reports of clinically apparent liver injury attributed to its use.
Interestingly, in the large preregistration trial of fostemsavir, elevations in serum aminotransferase levels were particularly noted in patients with coinfection with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The deaths from liver disease in this trial appeared to be due to worsening of the coinfection during therapy. Clearly, patients with HBV or HCV coinfection should be treated for those viral infections before or concurrent with antiretroviral therapy with fostemsavir.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Protein Binding
Temsavir is approximately 88.4% protein-bound in plasma, primarily to serum albumin.

[1]. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrobial Agents and Chemotherapy (2012), 56(7), 3498-3507.

[2]. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis. 2012 Oct 1;206(7):1002-11.

BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.[1]

C24H23N7O4

473.48392

473.181

C, 60.88; H, 4.90; N, 20.71; O, 13.52

701213-36-7

Temsavir;701213-36-7;Fostemsavir Tris;864953-39-9; 864953-29-7(free base); 864953-39-9 (tromethamine) ; 864953-31-1 (disodium); 942117-71-7 (dihydrate)

11317439

White to off-white solid powder.

1.5±0.1 g/cm3

787.6±70.0 °C at 760 mmHg

430.1±35.7 °C

0.0±2.7 mmHg at 25°C

1.722

-1.49

126.31

1

7

5

35

799

0

O=C(N1CCN(C(C2=CC=CC=C2)=O)CC1)C(C3=CNC4=C3C(OC)=CN=C4N5C=NC(C)=N5)=O

QRPZBKAMSFHVRW-UHFFFAOYSA-N

InChI=1S/C24H23N7O4/c1-15-27-14-31(28-15)22-20-19(18(35-2)13-26-22)17(12-25-20)21(32)24(34)30-10-8-29(9-11-30)23(33)16-6-4-3-5-7-16/h3-7,12-14,25H,8-11H2,1-2H3

1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione

BMS-626529; BMS 626529; BMS-626529; Temsavir (BMS-626529); 1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione; 4B6J53W8N3

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 : ≥ 16.67 mg/mL (~35.21 mM)

配方 1 中的溶解度: ≥ 1.67 mg/mL (3.53 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 16.7 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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: ≥ 1.67 mg/mL (3.53 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 16.7mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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: ≥ 1.67 mg/mL (3.53 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 16.7 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。