Tryptophan hydroxylase

体外活性：Telotristat（以前称为 LP-778902）是 LX1606（Telotristat etiprate）的活性代谢物，LX1606 是一种口服生物可利用的小分子色氨酸羟化酶 (TPH) 抑制剂，潜在体内 IC50 为 0.028 μM，并且具有抗血清素活性。 Telotristat 具有控制类癌综合征相关腹泻的活性。 Telotristat 通过抑制色氨酸羟化酶 (TPH) 发挥作用，减少胃肠道内外血清素的产生，而不影响大脑血清素水平。用 telotristat 阻断外周血清素合成可减轻化学和感染引起的肠道炎症的严重程度。激酶测定：Telotristat（以前称为 LP-778902）是 LX1606（Telotristat etiprate）的活性代谢物，LX1606 是一种口服生物可利用的小分子色氨酸羟化酶 (TPH) 抑制剂，体内 IC50 为 0.028 μM，具有抗血清素能作用活动。细胞测定：BON CBA 细胞在等体积的含 5% 牛血清的 DMEM 和 F12K 中生长 3-4 小时（20 K 细胞/孔），并添加浓度范围为 0.07 至 50 μM 的 telotristat。将细胞在 37°C 下孵育过夜。然后取 50 μM 培养上清液用于 5HTP 测量。将上清液与等体积的1M TCA混合，然后通过玻璃纤维过滤。将滤液加载到反相 HPLC 上进行 5HTP 浓度测量。通过用 Celltiter-Glo 发光细胞活力测定处理剩余的细胞来测量细胞活力。

telotristat ethy (15, 50, 150, 300 mg/kg, po, qd) 可降低外周血清素水平，但小鼠大脑中的血清素水平不降低。 Telotristat ethy（200 mg/kg，口服，每日一次）可显着保护小鼠免受炎症性肠病的侵害，并抑制 TNBS 攻击后血液中性粒细胞计数的上升。 IBD 小鼠模型的组织病理学评估证实，telotristat ethy（200 mg/kg，口服，每日一次）可以保护模型[1]。在空肠中，telotristat ethyl (15、50、150 和 300 mg/kg) 消耗 5-HT，但在大脑中则不然。然而，在用telotristat ethyl（200 mg/kg，口服）治疗的小鼠中，既没有发生组成性胃肠动力，也没有发生肠神经元的血清素（5-HT）消耗。由三硝基苯磺酸 (TNBS) 引起的结肠炎的严重程度可通过 telotristat ethyl (200 mg/kg) 减轻 [2]。

Animal information: C57Bl/6brd x 129SvEv F1 hybrid mice were used in all experiments. The studies were carried out with protocols approved by the Institutional Animal Care and Use Committee of Lexicon Pharmaceuticals, Inc.[1]
5-HT measurement: Blood was mixed in buffer containing 56 mM sodium ascorbate and 600 mM trichloroacetic acid, and jejunum tissues were homogenized in a buffer containing 300 mM trichloroacetic acid, 100 mM sodium acetate, pH 3.5, 0.01 mM EDTA, and 20 mM sodium bisulfate. The resulting cell lysates were centrifuged and the supernatants analyzed for 5-HT content using reverse phase HPLC with a C18 column and an in-line fluorescence detector. [1]
TNBS-IBD model: Animals were challenged via intra-rectal administration with 2% TNBS or left untreated as naïve controls. LX1606 and sulfasalazine were formulated in 0.25% methylcellulose and given to mice once daily via oral gavage starting 6 days before TNBS challenge and continuing during challenge. [1]
Blood neutrophil count: Blood was collected in EDTA by retro-orbital bleeding and complete cell counts were measured on a Veterinary cell counter. [1]
Histological analysis: Proximal and distal colon and cecum were collected, fixed in formalin, and sections were stained with hematoxylin and eosin. The sections were scored using a modified TJL system. [1]
Quantitative polymerase chain reaction (qPCR) analysis of cytokine expression: Total RNA was extracted from distal colon. Interested genes were analyzed by standard qPCR methods[1]

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Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation.[2]
Results: LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant.[2]

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Dissolved in 15% cyclodextrin or 0.25% methylcellulose; 300 mg/kg; p.o.

Male C57BL/6 mice and male C57 albino mice.

[1]. LX1606 (aka LX1032), a Novel Inhibitor of Serotonin Synthesis, Alleviates Development of Inflammatory Bowel Disease in a Preclinical Model.

[2]. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut, 2013.

Telotristat Etiprate is an orally bioavailable, small-molecule, tryptophan hydroxylase (TPH) inhibitor prodrug, with potential antiserotonergic activity. Upon administration, telotristat etiprate is converted to its active moiety, telotristat (LP-778902), which binds to and blocks the activity of TPH. This may result in a reduction in peripheral serotonin (5-HT) production and improvement of serotonin-mediated gastrointestinal effects such as severe diarrhea. TPH, the rate-limiting enzyme in serotonin biosynthesis, is overexpressed in carcinoid tumor cells.
See also: Telotristat (has active moiety).

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Drug Indication
Xermelo is indicated for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy.
Treatment of carcinoid syndrome

C27H26CLF3N6O3.C9H9NO3

754.15

753.228

C, 57.33; H, 4.68; Cl, 4.70; F, 7.56; N, 13.00; O, 12.73

1137608-69-5

Telotristat ethyl;1033805-22-9;Telotristat;1033805-28-5; 1137608-69-5 (etiprate) ; 1374745-52-4 (besilate)

25253377

White to off-white solid powder

145 °C

7.162

197.57

4

14

13

53

1020

2

O=C([C@H](CC1=CC=C(C=C1)C2=CC(O[C@H](C3=C(C=C(C=C3)Cl)N4C=CC(C)=N4)C(F)(F)F)=NC(N)=N2)N)OCC.O=C(C5=CC=CC=C5)NCC(O)=O

XSFPZBUIBYMVEA-CELUQASASA-N

InChI=1S/C27H26ClF3N6O3.C9H9NO3/c1-3-39-25(38)20(32)12-16-4-6-17(7-5-16)21-14-23(35-26(33)34-21)40-24(27(29,30)31)19-9-8-18(28)13-22(19)37-11-10-15(2)36-37;11-8(12)6-10-9(13)7-4-2-1-3-5-7/h4-11,13-14,20,24H,3,12,32H2,1-2H3,(H2,33,34,35);1-5H,6H2,(H,10,13)(H,11,12)/t20-,24+;/m0./s1

2-benzamidoacetic acid;ethyl (2S)-2-amino-3-[4-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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: ≥ 10 mg/mL (13.26 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 100.0 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: ≥ 10 mg/mL (13.26 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 100.0 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。