Tryptophan hydroxylase

Serotonin levels in the peripheral are decreased by telotristat ethyl (15, 50, 150, 300 mg/kg, po, qd), but not in the mouse brain. Telotristat ethyl (200 mg/kg po, qd) significantly protects mice against inflammatory bowel disease and inhibits the rise in blood neutrophil counts seen following TNBS challenge. Histopathological evaluation of a mouse model of IBD confirms that telotristat ethyl (200 mg/kg po, qd) protects the model [1]. In the jejunum, telotristat ethyl (15, 50, 150, and 300 mg/kg) depletes 5-HT, but not in the brain. Nevertheless, neither constitutive gastrointestinal motility nor serotonin (5-HT) depletion of enteric neurons occurs in mice treated with telotristat ethyl (200 mg/kg, po). The severity of colitis caused by trinitrobenzene sulfonic acid (TNBS) is lessened by telotristat ethyl (200 mg/kg) [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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 10 mg/mL (13.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 10 mg/mL (13.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)