PICLAMILAST

Details

Stereochemistry	ACHIRAL
Molecular Formula	C18H18Cl2N2O3
Molecular Weight	381.253
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=C(OC2CCCC2)C=C(C=C1)C(=O)NC3=C(Cl)C=NC=C3Cl

InChI

InChIKey=RRRUXBQSQLKHEL-UHFFFAOYSA-N

InChI=1S/C18H18Cl2N2O3/c1-24-15-7-6-11(8-16(15)25-12-4-2-3-5-12)18(23)22-17-13(19)9-21-10-14(17)20/h6-10,12H,2-5H2,1H3,(H,21,22,23)

HIDE SMILES / InChI

Description
Sources: https://newdrugapprovals.org/2014/03/19/piclamilast/
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800004110 http://www.drugbank.ca/drugs/DB01791 https://www.ncbi.nlm.nih.gov/pubmed/7613200 https://www.ncbi.nlm.nih.gov/pubmed/9316851

Piclamilast (RP 73401), is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as asthma, dermatitis, rheumatoid arthritis. Emesis is the most commonly cited side effect of piclamilast.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Phosphodiesterase 4B 11 Target ID: CHEMBL275 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15576036	Inhibitor 8297	0.041 nM [IC50]
Phosphodiesterase 4D 14 Target ID: CHEMBL288 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15576036	Inhibitor 8297	0.021 nM [IC50]
Phosphodiesterase 4A 13 Target ID: CHEMBL254 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15339393	Inhibitor 8297
Phosphodiesterase 4 52 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8762090 \| https://www.ncbi.nlm.nih.gov/pubmed/11259554	Inhibitor 8297	0.0012 µM [IC50]
Cytochrome P450 2B6 19 Target ID: CHEMBL4729 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9316851	Substrate 661

Conditions

Condition	Modality	Highest Phase	Product
Allergic asthma 6 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16875702	Primary	Preclinical	Unknown Approved Use Unknown
Immunological dermatitis 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10748277 http://adisinsight.springer.com/drugs/800004110	Primary	Preclinical	Unknown Approved Use Unknown
Rheumatoid arthritis 316 Sources: http://adisinsight.springer.com/drugs/800004110 https://www.ncbi.nlm.nih.gov/pubmed/14998551	Primary	Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
The effect of selective phosphodiesterase inhibitors in comparison with other anti-asthma drugs on allergen-induced eosinophilia in guinea-pig airways.	1995 Feb	8535097
Pharmacological modulation of secondary mediator systems--cyclic AMP and cyclic GMP--on inflammatory hyperalgesia.	1999 Jun	10401557
Effects of several glucocorticosteroids and PDE4 inhibitors on increases in total lung eosinophil peroxidase (EPO) levels following either systemic or intratracheal administration in sephadex- or ovalbumin-induced inflammatory models.	2000 Aug	10850854
Role of p38 MAP kinase in LPS-induced airway inflammation in the rat.	2001 Apr	11309243
In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor.	2001 Apr	11259555
Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro.	2001 Apr	11259554
Requirement of additional adenylate cyclase activation for the inhibition of human eosinophil degranulation by phosphodiesterase IV inhibitors.	2001 Apr 6	11301054
Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.	2001 Jan 8	11140727
Effects of PDE4 inhibitors on lipopolysaccharide-induced priming of superoxide anion production from human mononuclear cells.	2001 Jun	11545248
Identification of substrate specificity determinants in human cAMP-specific phosphodiesterase 4A by single-point mutagenesis.	2001 Mar	11282454
[Inhibition of uterine contractions: new in vitro pharmacological approaches on the pregnant human myometrium].	2001 May-Jun	11475797
Is up-regulation of phosphodiesterase 4 activity by PGE2 involved in the desensitization of beta-mimetics in late pregnancy human myometrium?	2001 Nov	11701706
Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4- inhibiting properties.	2001 Oct 26	11606060
Modulation of eotaxin formation and eosinophil migration by selective inhibitors of phosphodiesterase type 4 isoenzyme.	2001 Sep	11564646
The selective phosphodiesterase 4 inhibitor RP 73-401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta release during acute lung injury in mice: the role of the balance between Tumor necrosis factor-alpha and interleukin-10.	2002 Apr	11907182
Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes--functional importance of phosphodiesterase 4.	2002 Feb	11834608
Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors.	2002 Jun	12067300
[Comparison of piclamilast with ciclamilast in bronchodilating and antiallergic effects].	2003 Aug	14521139
Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes.	2003 Jan 1	12464242
Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram.	2003 May	12704225
Antidepressant-induced increase in high-affinity rolipram binding sites in rat brain: dependence on noradrenergic and serotonergic function.	2003 Oct	12954819
Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients.	2004	15765929
[Phosphosdiesterase 4 inhibitors in the treatment of pulmonary diseases].	2004 Jan	14989829
Differential effect of phosphodiesterase IV inhibitor RP73401 on various inflammatory and immune responses relevent to rheumatoid arthritis.	2004 May	14998551
Phosphodiesterase IV inhibition by piclamilast potentiates the cytodifferentiating action of retinoids in myeloid leukemia cells. Cross-talk between the cAMP and the retinoic acid signaling pathways.	2004 Oct 1	15292163
Selective inhibition of purified human phosphodiesterase 4A expressed in yeast cell GL62 by ciclamilast, piclamilast, and rolipram.	2004 Sep	15339393
Pharmacological inhibition of phosphodiesterase 4 triggers ovulation in follicle-stimulating hormone-primed rats.	2005 Jan	15448112
Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors.	2006	16257550
Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo.	2006 Oct	16861399
Effects of ciclamilast, a new PDE 4 PDE4 inhibitor, on airway hyperresponsiveness, PDE4D expression and airway inflammation in a murine model of asthma.	2006 Oct 10	16956605
Inhibition of phosphodiesterase activity, airway inflammation and hyperresponsiveness by PDE4 inhibitor and glucocorticoid in a murine model of allergic asthma.	2006 Oct 26	16875702
Treating COPD with PDE 4 inhibitors.	2007	18268925
Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain.	2007 Nov 14	17658510
Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase.	2007 Oct 15	17659276
ABCD of the phosphodiesterase family: interaction and differential activity in COPD.	2008	19281073
Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.	2008	18941502
Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue.	2008 Mar	18342202
Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury.	2008 Mar	18094015
Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?	2008 Oct	18660832
Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury.	2009 Apr 29	19402887
PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER.	2010 Aug 9	20711499
Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition.	2010 May	20082309
Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice.	2010 May 5	20444277
Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness.	2011 Dec 8	22023548

Patents

Sample Use Guides

In Vivo Use Guide

1, 3 and 10 mg/kg were orally administered once daily

Route of Administration: Oral

In Vitro Use Guide

RP 73401 (IC50: 6.9 +/- 3.3 nM, n = 5) was 71 fold more potent than (+/-)-rolipram (IC50: 490 +/- 260 nM, n = 4) in inhibiting LPS-induced TNF alpha release from monocytes. RP 73401 (IC50: 2 nM) was 180 fold more potent than rolipram (IC50: 360 nM) in suppressing LPS (10 ng ml-1)-induced TNF alpha mRNA.

Name

Type

Language

PICLAMILAST

Official Name

English

BENZAMIDE, 3-(CYCLOPENTYLOXY)-N-(3,5-DICHLORO-4-PYRIDINYL)-4-METHOXY-

Systematic Name

English

RPR-73401

Code

English

3-(CYCLOPENTYLOXY)-N-(3,5-DICHLORO-4-PYRIDYL)-P-ANISAMIDE

Common Name

English

Piclamilast [WHO-DD]

Common Name

English

RP-73401

Code

English

PICLAMILAST [USAN]

Common Name

English

piclamilast [INN]

Common Name

English

RP73401

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C744