TELOTRISTAT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H22ClF3N6O3
Molecular Weight	546.929
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=NN(C=C1)C2=C(C=CC(Cl)=C2)[C@@H](OC3=NC(N)=NC(=C3)C4=CC=C(C[C@H](N)C(O)=O)C=C4)C(F)(F)F

InChI

InChIKey=NCLGDOBQAWBXRA-PGRDOPGGSA-N

InChI=1S/C25H22ClF3N6O3/c1-13-8-9-35(34-13)20-11-16(26)6-7-17(20)22(25(27,28)29)38-21-12-19(32-24(31)33-21)15-4-2-14(3-5-15)10-18(30)23(36)37/h2-9,11-12,18,22H,10,30H2,1H3,(H,36,37)(H2,31,32,33)/t18-,22+/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.openaccessjournals.com/articles/telotristat-etiprate-a-novel-inhibitor-of-serotonin-synthesis-for-the-treatment-of-carcinoid-syndrome.pdf
Curator's Comment: Description was created using several sources including: http://www.lexpharma.com/media-center/news/525-fda-extends-pdufa-date-for-telotristat-etiprate-for-the-treatment-of-carcinoid-syndrome; https://www.ncbi.nlm.nih.gov/pubmed/25012985

Telotristat (telotristat etiprate) is an ethyl ester prodrug which is hydrolyzed to its active moiety LP-778902 both in vivo and in vitro. Telotristat etiprate is an orally bioavailable, small-molecule, tryptophan hydroxylase (TPH) inhibitor. It is the first investigational drug in clinical studies to target TPH, an enzyme that triggers the excess serotonin production within metastatic neuroendocrine tumor (mNET) cells leading to carcinoid syndrome. Unlike existing treatments of carcinoid syndrome which reduce the release of serotonin outside tumor cells, telotristat etiprate reduces serotonin production within the tumor cells. By specifically inhibiting serotonin production telotristat may provide patients with more control over their disease. Telotristat etiprate has received Fast Track and Orphan Drug designation from the U.S. Food and Drug Administration and has been granted priority review by the FDA with a Prescription Drug User Fee Act (PDUFA) target action date of February 28, 2017.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Carboxylesterase 2 9 Target ID: CHEMBL2217 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf	Substrate 661
tryptophan hydroxylase 2 4 Target ID: 121278.0 Gene Symbol: TPH2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf	Inhibitor 8297	1210.0 nM [IC50]
tryptophan hydroxylase 1 4 Target ID: 7166.0 Gene Symbol: TPH1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf	Inhibitor 8297	800.0 nM [IC50]
tryptophan hydroxylase 2 4 Target ID: 121278.0 Gene Symbol: TPH2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf	Inhibitor 8297	32.0 nM [IC50]
tryptophan hydroxylase 1 4 Target ID: 7166.0 Gene Symbol: TPH1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf	Inhibitor 8297	28.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Carcinoid syndrome 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf	Curative		Approved 8429	XERMELO Approved Use Xermelo is a tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Launch Date 1.48815361E12

C_max

Value	Dose	Co-administered	Analyte	Population
610 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TELOTRISTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
2320 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TELOTRISTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
5 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TELOTRISTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TELOTRISTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

Doses

Dose	Population	Adverse events
500 mg 3 times / day steady, oral Highest studied dose Dose: 500 mg, 3 times / day Route: oral Route: steady Dose: 500 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25636046	unhealthy, adult n = 14 Health Status: unhealthy Condition: carcinoid syndrome Age Group: adult Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/25636046	Disc. AE: Abdominal pain, Shortness of breath... AEs leading to discontinuation/dose reduction: Abdominal pain (1 patient) Shortness of breath (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/25636046
500 mg 3 times / day steady, oral Highest studied dose Dose: 500 mg, 3 times / day Route: oral Route: steady Dose: 500 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	unhealthy, adult n = 70 Health Status: unhealthy Condition: carcinoid syndrome Age Group: adult Population Size: 70 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	Disc. AE: Gastrointestinal disorders, Skin and subcutaneous tissue disorders... AEs leading to discontinuation/dose reduction: Gastrointestinal disorders (7.1%) Skin and subcutaneous tissue disorders (1.4%) Cardiac disorders (1.4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf
250 mg 3 times / day steady, oral Recommended Dose: 250 mg, 3 times / day Route: oral Route: steady Dose: 250 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	unhealthy, adult n = 140 Health Status: unhealthy Condition: carcinoid syndrome Age Group: adult Population Size: 140 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	Disc. AE: Abdominal pain, GGT increased... AEs leading to discontinuation/dose reduction: Abdominal pain (4.3%) GGT increased (2.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf
250 mg 3 times / day steady, oral Recommended Dose: 250 mg, 3 times / day Route: oral Route: steady Dose: 250 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	unhealthy, adult n = 70 Health Status: unhealthy Condition: carcinoid syndrome Age Group: adult Population Size: 70 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf	Disc. AE: Gastrointestinal disorders, Psychiatric disorders... AEs leading to discontinuation/dose reduction: Gastrointestinal disorders (10%) Psychiatric disorders (2.9%) Infections and infestations (2.9%) Skin and subcutaneous tissue disorders (1.4%) Hepatobiliary disorders (1.4%) Metabolism and nutrition disorders (1.4%) Renal and urinary disorders (1.4%) Respiratory, thoracic and mediastinal disorders (1.4%) Vascular disorders (1.4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000MedR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 CYP2C8 911 CYP2E1 882 CYP2B6 810 P-gp 1461 BCRP 699 OCT1 512 OCT2 647 OAT1 599 OAT3 642 OATP1B1 788 OATP1B3 706 BSEP 402	P-gp 1537 BCRP 561	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7.0	likely
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7.0	likely	TELOTRISTAT 4
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7.0	likely
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7.0	likely	TELOTRISTAT 4
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7, 38	likely
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=8 Page: 7.0	likely	TELOTRISTAT 4
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	no	TELOTRISTAT 4
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	no	TELOTRISTAT 4
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	no	TELOTRISTAT 4
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	no	TELOTRISTAT 4
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	no	TELOTRISTAT 4
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	unlikely	TELOTRISTAT 4
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak	TELOTRISTAT 4
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak	TELOTRISTAT 4
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	weak	TELOTRISTAT 4
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208794s000lbl.pdf#page=10 Page: 10.0	yes
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	yes
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36.0	yes	TELOTRISTAT 4
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=29 Page: 36, (ClinPharm) 28-30, 38	yes		no (co-administration study) Comment: 79% inihibition at 1 mcM, 30 min incubation (cytochrome P450isozymes using specific fluorometric substrates or human liver microsomal samples w/LC-MS/MS analysis), When 3 mg midazolam was coadministered orally after 5 day treatment with telotristat ethyl 500 mg three times daily (twice the recommended dosage), the mean Cmax , and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively, compared to administration of midazolam alone. The mean Cmax , and AUC0-inf for the active metabolite, 1’-hydroxymidazolam, were also decreased by 34%, and 48%, respectively. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=29 Page: 36, (ClinPharm) 28-30, 38
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=31 Page: 30-31, 39	yes		unlikely (co-administration study) Comment: Following co-administration with telotristat ethyl (500 mg TID x 5 days (twice the recommended dose)), mean Cmax, and AUC0-inf for fexofenadine (180 mg with the final dose of telotristat ethyl) were 15.6%, and 14.3% higher, respectively compared to administration alone. Telotristat ethyl exhibited a lower level of P-gp inhibition in humans (<1.25-fold) that not clinically meaningful. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000ClinPharmR.pdf#page=31 Page: 30-31, 39

Drug as victim

Target	Modality	Activity	Metabolite
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36-37	likely	TELOTRISTAT 4
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36-37	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36-37	no	TELOTRISTAT 4
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=43 Page: 36-37	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=32 Page: 25.0
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208794Orig1s000PharmR.pdf#page=32 Page: 25.0		TELOTRISTAT 4

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA008TH4	https://www.aablocks.com/goods/Goods/detail?id=AA008TH4
ApexBio Technology	B3247	http://www.apexbt.com/telotristat.html
BioCrick	BCC5128	http://www.biocrick.com/Telotristat-BCC5128.html
Chem Scene	CS-2408	http://www.chemscene.com/1033805-28-5.html
Chemspace	CSSB00025704745	https://chem-space.com/CSSB00025704745
DC Chemicals	DC23164	http://www.dcchemicals.com/product_show-DC23164.html
Excenen	EX-A1620	http://www.excenen.com/searchresultlist.php?id=1033805-28-5
Lab Network	LN01306658	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01306658
MedChem Express	HY-13055B	https://www.medchemexpress.com/telotristat.html
Smolecule	S544877	http://www.smolecule.com/products/s544877
Smolecule	S746675	https://www.smolecule.com/products/s746675
THE BioTek	bt-283998	https://www.thebiotek.com/product/inhibitors/bt-283998
abcr GmbH	AB463154	http://www.abcr.com/shop/en/AB463154
eNovation Chemicals	D552488	https://www.enovationchem.com/ProductDetails.asp?ProductID=D552488
eNovation Chemicals	D678474	https://www.enovationchem.com/ProductDetails.asp?ProductID=D678474

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

Two 250 mg telotristat etiprate tablets three times daily over 12 weeks

Route of Administration: Oral

In Vitro Use Guide

Unknown

Name

Type

Language

TELOTRISTAT

Official Name

English

4-(2-AMINO-6-((1R)-1-(4-CHLORO-2-(3-METHYL-1H-PYRAZOL-1-YL)PHENYL)-2,2,2- TRIFLUOROETHOXY)PRYRIMIDIN-4-YL)-L-PHENYLALANINE

Common Name

English

LP-778902

Code

English

TELOTRISTAT [USAN]

Common Name

English

L-PHENYLALANINE, 4-(2-AMINO-6-((1R)-1-(4-CHLORO-2-(3-METHYL-1H-PYRAZOL-1-YL)PHENYL)- 2,2,2-TRIFLUOROETHOXY)-4-PRYRIMIDINYL)-

Common Name

English

telotristat [INN]

Common Name

English

LP 778902

Code

English

TELOTRISTAT [MI]

Common Name

English

2S)-2-AMINO-3-(4-(2-AMINO-6-(((1R)-1-(4-CHLORO-2-(3-METHYL-1H-PYRAZOL-1-YL)PHENYL)-2,2,2-TRIFLUOROETHYL)OXY)PYRIMIDIN-4-YL)PHENYL)PROPANOIC ACID

Common Name

English

Telotristat [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C471