BIBX 1382

BIBX 1382 targets the intracellular tyrosine kinase domain of epidermal growth factor receptor (EGFR); [1]
BIBX 1382 is a selective EGFR kinase inhibitor that does not block the activity of other tyrosine kinases; inhibits EGFR with half-maximally effective doses in the nanomolar range in EGFR-expressing KB cells (exact value not specified) [2]

Falnidamol (BIBX 1382) 在 KB 细胞有丝分裂测定中表现出抗增殖活性 [2]。

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BIBX 1382可抑制EGFR的细胞内酪氨酸激酶结构域，逆转由EGFR过表达和组成性激活导致的异常酶活性 [1]
BIBX 1382能够强效且选择性地抑制胸腺嘧啶核苷掺入表达EGFR的KB细胞，半数有效剂量处于纳摩尔级别；该药物为选择性EGFR激酶抑制剂，不会阻断其他酪氨酸激酶的活性 [2]

治疗两周后，法尼达莫（BIBX 1382；口服；10 mg/kg/天；16天）完全抑制人A431异种移植物中肿瘤的生长，相应的T/C值为15%[2]。在携带 A431 异种移植物的小鼠中，法尼达莫（50 mg/kg/天）会导致 EGF 受体去磷酸化[2]。法尼达莫（口服；10 mg/kg/天；16 天）的 C4h 和 C24h 分别为 2222 和 244 nM [2]。

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经口服给予BIBX 1382可抑制无胸腺小鼠体内已建立的人类异种移植瘤（外阴鳞状细胞癌、头颈部鳞状细胞癌）的生长；肿瘤生长受抑制的同时，体内pEGFR和Ki-67水平降低 [2]

为评估BIBX 1382对表达EGFR的KB细胞的作用，开展胸腺嘧啶核苷掺入实验以检测细胞增殖情况：通过测定胸腺嘧啶核苷掺入细胞DNA的量来反映药物的抗增殖效果，结果显示BIBX 1382可选择性且强效地抑制KB细胞的胸腺嘧啶核苷掺入，半数有效剂量处于纳摩尔级别。此外，还检测了表皮生长因子诱导的EGFR磷酸化水平，以及下游信号分子（丝裂原活化蛋白激酶激酶（MAPK/细胞外信号调节激酶激酶）和MAPK）的活化情况，以此验证BIBX 1382对EGFR活性及其下游信号通路的抑制作用 [2]

Animal/Disease Models: Five- to sixweeks old athymic NMRI-nu/nu female mice (21-31 g) with A431, FaDu, or HN5 cells[2]
Doses: 10 mg/kg
Route of Administration: po; daily; 16 days
Experimental Results: Completely suppressed tumor growth of human A431 xenografts with respective T/C values of 15 and 6% after 2 weeks of treatment.

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Animal/Disease Models: Five- to sixweeks old athymic NMRI-nu/nu female mice (21–31 g) with A431 cells[2]
Doses: 10 mg/kg (pharmacokinetic/PK Analysis)
Route of Administration: po; daily; 16 days
Experimental Results: The C4h is 2222 nM and the C24h is 244 nM.

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Athymic mice were used to establish human xenograft models (vulval and head and neck squamous cell carcinomas). BIBX 1382 was administered to the mice via oral route (specific dosage, dissolution formula/dosage form not specified). The growth of xenograft tumors was monitored to evaluate the in vivo anti-tumor efficacy of BIBX 1382; after the experiment, tumor tissues were collected to detect the levels of pEGFR and Ki-67 by relevant methods to explore the mechanism of tumor growth inhibition [2]

Oral administration of BIBX 1382 in humans yielded plasma levels far below those expected to be efficacious; a preclinically unknown, pharmacologically inactive metabolite was identified from the urine of one patient and was found to be abundant in patient plasma [1]

In humans receiving continuous daily oral administration of BIBX 1382, reversible, dose-dependent increase of liver enzymes occurred (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3); this liver enzyme elevation was dose-limiting [1]

[1]. Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration. Eur J Cancer. 2002 May;38(8):1072-80.

[2]. Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives. J Pharmacol Exp Ther. 2004 Nov;311(2):502-9.

N4-(3-chloro-4-fluorophenyl)-N6-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidine-4,6-diamine is a substituted aniline.
Falnidamol has been used in trials studying the treatment of Unspecified Adult Solid Tumor, Protocol Specific.
Falnidamol is a pyrimido-pyrimidine with antitumor activity. BIBX 1382 inhibits the intracellular tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) thus specifically reversing the aberrant enzymatic activity from overexpressed and constitutively activated EGFR, and subsequently inhibiting cell proliferation and inducing cell differentiation.

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BIBX 1382 is a pyrimido-pyrimidine derivative; a phase I and pharmacokinetic study of BIBX 1382 was carried out in humans with miscellaneous solid tumours (11 patients, 7 females, 4 males, median age 63 years, WHO PS 0:5 patients, 1:6 patients), using an accelerated titration design from the first toxicities onwards followed by a modified Fibonacci scheme for dose escalation (dosages: 25 mg, 50 mg, 100 mg, 200 mg, 150 mg; cycles defined as 28 days of treatment, median number of cycles per patient: 2, range 1-7). The trial was discontinued due to dose-limiting liver enzyme increase, low bioavailability, and detection of a pharmacologically inactive metabolite [1]
BIBX 1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine) is a pyrimidopyrimidine derivative; it belongs to a new class of selective EGFR kinase inhibitors, and the pyrimidopyrimidine structural class represents an interesting scaffold for the design of EGFR inhibitors [2]

C18H19CLFN7

387.84

387.137

196612-93-8

6918508

Light yellow to khaki solid powder

594ºC at 760mmHg

313.1ºC

3.15E-12mmHg at 25°C

1.7

5.149

78.86

2

8

4

27

479

0

FTFRZXFNZVCRSK-UHFFFAOYSA-N

InChI=1S/C18H19ClFN7/c1-27-6-4-11(5-7-27)25-18-21-9-15-16(26-18)17(23-10-22-15)24-12-2-3-14(20)13(19)8-12/h2-3,8-11H,4-7H2,1H3,(H,21,25,26)(H,22,23,24)

4-N-(3-chloro-4-fluorophenyl)-6-N-(1-methylpiperidin-4-yl)pyrimido[5,4-d]pyrimidine-4,6-diamine

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: ≥ 1.67 mg/mL (4.31 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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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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。