DEXTOFISOPAM

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H26N2O4
Molecular Weight	382.4528
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC[C@@H]1C2=CC(OC)=C(OC)C=C2C(=NN=C1C)C3=CC=C(OC)C(OC)=C3

InChI

InChIKey=RUJBDQSFYCKFAA-HNNXBMFYSA-N

InChI=1S/C22H26N2O4/c1-7-15-13(2)23-24-22(14-8-9-18(25-3)19(10-14)26-4)17-12-21(28-6)20(27-5)11-16(15)17/h8-12,15H,7H2,1-6H3/t15-/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.wikinvest.com/stock/Pharmos_(PARS)/Filing/10-K/2008/F5438184 | http://www.medscape.com/viewarticle/568560 | https://www.ncbi.nlm.nih.gov/pubmed/17973974

Dextofisopam, a non-serotonergic agent currently being evaluated for the treatment of irritable bowel syndrome (IBS), is the R-enantiomer of racemic tofisopam, a molecule marketed and used safely outside the United States for over three decades for multiple indications including IBS. Dextofisopam represents a novel, first-in-class opportunity with a positive proof-of-concept study in an arena where there are few compounds with unique approaches or positive efficacy results. By structure, Dextofisopam is a member of the homophthalazine class; Dextofisopam binds to specific receptors in areas of the brain affecting autonomic function, including gastrointestinal (GI) function. Unlike the two 5-HT3 or 5-HT4 mediated IBS therapies currently available, both with significant safety concerns, Dextofisopam novel non-serotonergic activity offers a unique and innovative approach to IBS treatment. Recent studies have indicated that dextofisopam binds to a novel binding site within the central nervous system that may be responsible for mediating its actions. This receptor has been characterized as the 2,3-benzodiazepine receptor, which is distinct from the classical 1,4 or 1,5-benzodiazepine receptor. Dextofisopam has no significant binding at other receptors or ion channels

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GABA-A receptor; benzodiazepine site 38 Target ID: CHEMBL2109243 Sources: http://www.genome.jp/dbget-bin/www_bget?dr:D03737 \| http://www.crystalsoftwaredesign.com/VelaPharm/images/ACG.pdf	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Irritable bowel syndrome 60 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17973974 http://adisinsight.springer.com/drugs/800017944	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
1508 ng/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1251 ng/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
756 ng/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
402 ng/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	200 mg 2 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
3338 ng × h/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3490 ng × h/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1729 ng × h/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
844 ng × h/mL OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	200 mg 2 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
10.1 h OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10.15 h OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.2 h OTHER https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease	200 mg 2 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DEXTOFISOPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease Page: p.2	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease Page: p.2	Sources: https://www.researchgate.net/publication/228774168_The_potential_of_dextofisopam_for_treatment_of_irritable_bowel_syndrome_and_inflammatory_bowel_disease Page: p.2
200 mg 2 times / day multiple, oral Studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17973974 Page: p.203	unhealthy, ADULT n = 66 Health Status: unhealthy Condition: irritable bowel syndrome Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 66 Sources: https://pubmed.ncbi.nlm.nih.gov/17973974 Page: p.203	Disc. AE: Pancreatitis... AEs leading to discontinuation/dose reduction: Pancreatitis (1.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/17973974 Page: p.203

AEs

AE	Significance	Dose	Population
Pancreatitis	1.5% Disc. AE	200 mg 2 times / day multiple, oral Studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17973974 Page: p.203	unhealthy, ADULT n = 66 Health Status: unhealthy Condition: irritable bowel syndrome Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 66 Sources: https://pubmed.ncbi.nlm.nih.gov/17973974 Page: p.203

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP3A5 395 CYP2C19 991

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17646282/	likely
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17646282/	major [Km 20 uM]
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17646282/	major [Km 7.6 uM]
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17646282/	yes [Km 0.9 uM]
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17646282/	yes [Km 17 uM]

PubMed

Title	Date	PubMed
Gateways to clinical trials.	2005 Apr	15834452
Personal view: adequate relief as a primary endpoint in irritable bowel syndrome.	2006 Apr 1	16573790
Gateways to clinical trials.	2006 Oct	17136234
Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome.	2008 Jan 15	17973974

Patents

Sample Use Guides

In Vivo Use Guide

100, 200, and 300 mg BID for 12 weeks

Route of Administration: Oral

In Vitro Use Guide

Incubations containing 500 ng/ml (1.3 uM) (R)-tofisopam (Dextofisopam) were carried out with 0.05, 0.2, and 1.0 mg/ml pooled human liver microsomes.

Name

Type

Language

DEXTOFISOPAM

Official Name

English

dextofisopam [INN]

Common Name

English

DEXTOFISOPAM [USAN]

Common Name

English

5H-2,3-BENZODIAZEPINE, 1-(3,4-DIMETHOXYPHENYL)-5-ETHYL-7,8-DIMETHOXY-4-METHYL, (5R)

Common Name

English

R-TOFISOPAM

Code

English

(+)-(5R)-1-(3,4-DIMETHOXYPHENYL)-5-ETHYL-7,8-DIMETHOXY-4-METHYL-5H-2,3-BENZODIAZEPINE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29698