PONESIMOD

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C23H25ClN2O4S
Molecular Weight	460.974
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	2
Charge	0

SHOW SMILES / InChI

SMILES

CCC\N=C1/S\C(=C/C2=CC=C(OC[C@H](O)CO)C(Cl)=C2)C(=O)N1C3=CC=CC=C3C

InChI

InChIKey=LPAUOXUZGSBGDU-STDDISTJSA-N

InChI=1S/C23H25ClN2O4S/c1-3-10-25-23-26(19-7-5-4-6-15(19)2)22(29)21(31-23)12-16-8-9-20(18(24)11-16)30-14-17(28)13-27/h4-9,11-12,17,27-28H,3,10,13-14H2,1-2H3/b21-12-,25-23-/t17-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C23H25ClN2O4S
Molecular Weight	460.974
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	2
Optical Activity	UNSPECIFIED

Description

Ponesimod is an experimental drug for the treatment of multiple sclerosis (MS) graft-versus-host disease and psoriasis. It acts on certain types of white blood cells (lymphocytes) which are involved in the autoimmune attack on myelin seen in multiple sclerosis (MS). Ponesimod is an orally active, reversible, and selective sphingosine-1-phosphate receptor (S1PR1) modulator. The drug is in phase II clinical trial for the treatment of graft-versus-host disease. In addition, the phase III clinical trial comparing ponesimod to teriflunomide in relapsing-remitting MS is ongoing.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sphingosine 1-phosphate receptor Edg-1 12	Modulator 828		5.0 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple sclerosis 104	Primary		Approved 8,429	PONVORY

C_max

Value	Dose	Analyte	Population
48.55 ng/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
61.4 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
37.1 ng/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
48.5 ng/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
61.4 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
3.4 ng/mL	1 mg single, oral	PONESIMOD plasma	Homo sapiens
13.7 ng/mL	3 mg single, oral	PONESIMOD plasma	Homo sapiens
27.2 ng/mL	8 mg single, oral	PONESIMOD plasma	Homo sapiens
71 ng/mL	20 mg single, oral	PONESIMOD plasma	Homo sapiens
163 ng/mL	50 mg single, oral	PONESIMOD plasma	Homo sapiens
274 ng/mL	75 mg single, oral	PONESIMOD plasma	Homo sapiens
20.3 ng/mL	5 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
48.5 ng/mL	10 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
91.7 ng/mL	20 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
40.3 ng/mL	5 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
88.3 ng/mL	10 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
207 ng/mL	20 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
46.8 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
138 ng/mL	20 mg single, oral	PONESIMOD plasma	Homo sapiens
292 ng/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
411 ng/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
54.7 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
51.4 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
49.2 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
48.2 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
46.8 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
54.5 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
50 ng/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
194 ng/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
196 ng/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
1246 ng × h/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
2124 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
1028 ng × h/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
1335 ng × h/mL	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
2236 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
96 ng × h/mL	1 mg single, oral	PONESIMOD plasma	Homo sapiens
405 ng × h/mL	3 mg single, oral	PONESIMOD plasma	Homo sapiens
913 ng × h/mL	8 mg single, oral	PONESIMOD plasma	Homo sapiens
2344 ng × h/mL	20 mg single, oral	PONESIMOD plasma	Homo sapiens
5266 ng × h/mL	50 mg single, oral	PONESIMOD plasma	Homo sapiens
9153 ng × h/mL	75 mg single, oral	PONESIMOD plasma	Homo sapiens
292 ng × h/mL	5 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
684 ng × h/mL	10 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
1318 ng × h/mL	20 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
643 ng × h/mL	5 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
1400 ng × h/mL	10 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
3473 ng × h/mL	20 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
667 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
2085 ng × h/mL	20 mg single, oral	PONESIMOD plasma	Homo sapiens
4277 ng × h/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
6325 ng × h/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
2190 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
3320 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
5070 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
1650 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
1587 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
1773 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
1554 ng × h/mL	10 mg single, oral	PONESIMOD plasma	Homo sapiens
6719 ng × h/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens
7627 ng × h/mL	40 mg single, oral	PONESIMOD plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
27.6 h	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
32.9 h	5 mg single, intravenous	PONESIMOD plasma	Homo sapiens
31.7 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
21.7 h	1 mg single, oral	PONESIMOD plasma	Homo sapiens
30.1 h	3 mg single, oral	PONESIMOD plasma	Homo sapiens
33.4 h	8 mg single, oral	PONESIMOD plasma	Homo sapiens
27.7 h	20 mg single, oral	PONESIMOD plasma	Homo sapiens
28.8 h	50 mg single, oral	PONESIMOD plasma	Homo sapiens
31.4 h	75 mg single, oral	PONESIMOD plasma	Homo sapiens
30.9 h	5 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
32.1 h	10 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
32.7 h	20 mg 1 times / day multiple, oral	PONESIMOD plasma	Homo sapiens
33.5 h	40 mg single, oral	PONESIMOD plasma	Homo sapiens
45.7 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
55.6 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
80.5 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
31.6 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
34.4 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
27.9 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
26.4 h	10 mg single, oral	PONESIMOD plasma	Homo sapiens
28.9 h	40 mg single, oral	PONESIMOD plasma	Homo sapiens
33.1 h	40 mg single, oral	PONESIMOD plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.42%			PONESIMOD plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
100 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT	Other AEs: Lethargy, Sensory disturbance...
20 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Dyspnea, ALT increased... Other AEs: Headache, Drug-induced liver injury...
20 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Macular edema, Dyspnea... Other AEs: Abdominal pain, Hepatocellular injury...
20 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Macular edema, ALT increased... Other AEs: Abdominal pain upper, Appendicitis...
10 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT	Disc. AE: Unintended pregnancy, Multiple sclerosis...

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AEs

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AE	Significance	Dose	Population
Lethargy	1 pt	100 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT
Sensory disturbance	8.3%	100 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT
Somnolence	8.3%	100 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT
Hypertension	2 patients Disc. AE	20 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT
Lymphocyte count decreased	2 patients Disc. AE	20 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inducer 389 inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
UGT2B7 146 UGT1A1 204 Efflux/Uptake transporters CYP2C8 911 CYP2C19 1,478 OATP1B3 706 CYP2J2 16 CYP2E1 882 CYP1A2 1,524 CYP2B6 810 OCT2 647 MATE1 306 CYP2A6 707 OATP1B1 788 OCT1 512 MATE2-K 9 BCRP 699 P-gp 1,461 OAT1 599 OAT3 642	UGT1A10 291 UGT2B17 213 UGT2B10 127 UGT1A8 283 UGT2B15 203 CYP3A5 395 UGT1A3 422 CYP2J2 56 OATP1B1 406 ALDH1A1 P-gp 1,537 UGT1A1 418 CYP4F12 3 OATP1B3 350 UGT2B7 389 UGT1A4 347 BCRP 561 CYP4F3A UGT2B4 249 UGT1A6 307 UGT1A7 236 UGT1A9 380	CYP2B6 547 CYP1A2 701

Drug as perpetrator

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Target	Modality	Activity
CYP2A6 739	inhibitor 3,277	no [IC50 >100 uM]
OAT1 603	inhibitor 3,277	no [IC50 >100 uM]
OAT3 644	inhibitor 3,277	no [IC50 >100 uM]
OCT1 543	inhibitor 3,277	no [IC50 >100 uM]
OCT2 648	inhibitor 3,277	no [IC50 >100 uM]

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Drug as victim

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Target	Modality	Activity
UGT1A3 422	substrate 3,367	minor
UGT1A4 347	substrate 3,367	minor
UGT2B4 249	substrate 3,367	minor
BCRP 561	substrate 3,367	no
OATP1B1 406	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626
hERG 1,647	inhibitor 1,626		ACT-338375

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PubMed

PubMed

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Title	Date	PubMed
[Psoriatic arthritis : Drugs of the (near) future].	2017 Aug	28681115
Ponesimod, a selective sphingosine 1-phosphate (S1P(1)) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition.	2018 May	28489480
Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1.	2018 Oct 15	30143424
Oral small molecules for psoriasis.	2018 Sep	30215633
Oral Therapies for Multiple Sclerosis.	2019 Jan 2	29500302

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Sample Use Guides

In Vivo Use Guide

The recommended maintenance dosage is 20 mg taken orally once daily.

Route of Administration: Oral

In Vitro Use Guide

Ponesimod had an EC50 of 5.7 nM for the human S1P1 receptor compared to an EC50 of 25.3 nM for the endogenous ligand S1P, but had considerably less potency against human S1P2 S1P3, S1P4 and S1P5 receptors (EC50s 59.1 to > 10,000 nM)

Substance Class	Chemical
Record UNII	5G7AKV2MKP
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PONESIMOD

Official Name

English

5-(3-CHLORO-4-(((2R)-2,3-DIHYDROXYPROPYL)OXY)BENZ-(Z)-YLIDENE)-2-((Z)-PROPYLIMINO)-3-(O-TOLYL)THIAZOLIDIN-4-ONE

Common Name

English

(2Z,5Z)-5-(3-CHLORO-4-((2R)-2,3-DIHYDROXYPROPOXY)BENZYLIDENE)-3-(2-METHYLPHENYL)-2-(PROPYLIMINO)-1,3-THIAZOLIDIN-4-ONE

Systematic Name

English

PONESIMOD [ORANGE BOOK]

Common Name

English

ACT-128800

Code

English

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Classification Tree

Code System

Code

Pharmacologic Substance

NCI_THESAURUS

C308

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Code System

Code

Type

Description

ChEMBL

CHEMBL1096146

PRIMARY

DRUG BANK

DB12016

PRIMARY

EPA CompTox

DTXSID50234631

PRIMARY

WIKIPEDIA

Ponesimod

PRIMARY

NCI_THESAURUS

C96534

PRIMARY

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					5G7AKV2MKP

PONESIMOD

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Referenced Substance
ORAL BIOAVAILABILITY	PHARMACOKINETIC	83.8 % (average)	`5G7AKV2MKP` PONESIMOD

Biological Half-life	PHARMACOKINETIC	33 hours (average)	`5G7AKV2MKP` PONESIMOD

Tmax	PHARMACOKINETIC	[2 to 4] hours (average)	`5G7AKV2MKP` PONESIMOD

Volume of Distribution	PHARMACOKINETIC	160 LITERS (average)	`5G7AKV2MKP` PONESIMOD

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator