TOLAFENTRINE

Details

Stereochemistry	UNKNOWN
Molecular Formula	C28H31N3O4S
Molecular Weight	505.628
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@]12CCN(C)C[C@@]1([H])C3=C(C=C(OC)C(OC)=C3)C(=N2)C4=CC=C(NS(=O)(=O)C5=CC=C(C)C=C5)C=C4

InChI

InChIKey=FVZJIAUYFDQQKJ-DQEYMECFSA-N

InChI=1S/C28H31N3O4S/c1-18-5-11-21(12-6-18)36(32,33)30-20-9-7-19(8-10-20)28-23-16-27(35-4)26(34-3)15-22(23)24-17-31(2)14-13-25(24)29-28/h5-12,15-16,24-25,30H,13-14,17H2,1-4H3/t24-,25-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16262900 | https://www.ncbi.nlm.nih.gov/pubmed/21382892

Tolafentrine is phosphodiesterase 3/4 (PDE3/4) inhibitor. Treatment of endothelial cells with tolafentrine significantly decreased asymmetrical dimethylarginine-induced apoptosis via a cAMP/PKA-dependent pathway by induction of dimethylarginine dimethylaminohydrolase 2 (DDAH2). Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities in rats, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. Tolafentrine was developed as therapeutic agent for the treatment of asthma. However, this development was discontinued.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phosphodiesterase 4 52 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12441759 \| https://www.scbt.com/scbt/product/tolafentrine-139308-65-9	Inhibitor 8297
Phosphodiesterase 3 60 Target ID: CHEMBL2094125 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12441759 \| https://www.scbt.com/scbt/product/tolafentrine-139308-65-9	Inhibitor 8297

PubMed

Title	Date	PubMed
Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions.	1995 Feb	7539697
In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors.	1997 May	9154331
Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.	1999 Nov	10556112
Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange.	2000 Feb	10640287
Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension. Maintenance of lung selectivity.	2001 Nov 1	11719312
Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension.	2002 Nov	12441759
Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation.	2003 Aug	12884304
Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension.	2004 Apr 30	15031263
Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration.	2005 Nov 1	16262900
Targeting dimethylarginine dimethylaminohydrolases in pulmonary arterial hypertension: a new approach to improve vascular dysfunction?	2011 Mar 22	21382895
cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases.	2011 Mar 22	21382892

Name

Type

Language

TOLAFENTRINE

Official Name

English

Tolafentrine [WHO-DD]

Common Name

English

(-)-4'-(CIS-1,2,3,4,4A,10B-HEXAHYDRO-8,9-DIMETHOXY-2-METHYLBENZO(C)(1,6)NAPHTHYRIDIN-6-YL)-P-TOLUENESULFONANILIDE

Common Name

English

BENZENESULFONAMIDE, N-(4-(1,2,3,4,4A,10B-HEXAHYDRO-8,9-DIMETHOXY-2-METHYLBENZO(C)(1,6)NAPHTHYRIDIN-6-YL)PHENYL)-4-METHYL-, CIS-(-)

Systematic Name

English

B-9004070

Code

English

BENZENESULFONAMIDE, N-(4-((4AR,10BS)-1,2,3,4,4A,10B-HEXAHYDRO-8,9-DIMETHOXY-2-METHYLBENZO(C)(1,6)NAPHTHYRIDIN-6-YL)PHENYL)-4-METHYL-, REL-(-)-

Systematic Name

English

BY-4070

Code

English

tolafentrine [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C744