XAMOTEROL FUMARATE

Details

Stereochemistry	RACEMIC
Molecular Formula	2C16H25N3O5.C4H4O4
Molecular Weight	794.8458
Optical Activity	( + / - )
Defined Stereocenters	0 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C\C(O)=O.OC(CNCCNC(=O)N1CCOCC1)COC2=CC=C(O)C=C2.OC(CNCCNC(=O)N3CCOCC3)COC4=CC=C(O)C=C4

InChI

InChIKey=QEDVGROSOZBGOZ-WXXKFALUSA-N

InChI=1S/2C16H25N3O5.C4H4O4/c2*20-13-1-3-15(4-2-13)24-12-14(21)11-17-5-6-18-16(22)19-7-9-23-10-8-19;5-3(6)1-2-4(7)8/h2*1-4,14,17,20-21H,5-12H2,(H,18,22);1-2H,(H,5,6)(H,7,8)/b;;2-1+

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2862938 | https://www.ncbi.nlm.nih.gov/pubmed/6128041
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/1967561 | https://www.ncbi.nlm.nih.gov/pubmed/1971596 | https://www.ncbi.nlm.nih.gov/pubmed/8465800

Xamoterol (ICI 118,587) is a partial agonist of beta1-adrenoceptors. Xamoterol acts on the cardiac beta 1-adrenergic receptor, modifies the response of the heart to variations in sympathetic activity. At rest, it produces modest improvements in cardiac contractility, relaxation, and filling without increase in myocardial oxygen demand. The improvements are maintained during exercise although the attendant tachycardia is attenuated. The beneficial effects of xamoterol on both systolic and diastolic function suggested that it would be effective in patients with mild-to-moderate heart failure, and this was demonstrated in small placebo-controlled studies where effort tolerance and symptoms were improved. Xamoterol produced improvements in exercise capacity, clinical signs, symptoms and quality of life with a low incidence of adverse experiences. Xamoterol is effective as monotherapy in heart failure.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Beta-1 adrenergic receptor 158 Target ID: CHEMBL213 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6128041 \| https://www.ncbi.nlm.nih.gov/pubmed/2862938	Partial Agonist 290

Conditions

Condition	Modality	Targets	Highest Phase	Product
Heart failure 103 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1967561 https://www.ncbi.nlm.nih.gov/pubmed/1971596 https://www.ncbi.nlm.nih.gov/pubmed/8465800	Primary		Approved 8429	CORWIN Approved Use Xamoterol (Fumarate) is primarily indicated in conditions like Heart failure.

PubMed

Title	Date	PubMed
Comparative analysis of beta-1 adrenoceptor agonist and antagonist potency and selectivity of cicloprolol, xamoterol and pindolol.	1987 Sep	2888869
Contrasting effects of single doses of pindolol and xamoterol on left ventricular diastolic function.	1989	2572264
Xamoterol improves the control of chronic atrial fibrillation in elderly patients.	1995 Jul	7484490
Cardioselective beta-blocker use in patients with reversible airway disease.	2001	11406056
Constitutive activity of the human beta(1)-adrenergic receptor in beta(1)-receptor transgenic mice.	2001 Oct	11562432
Rapid component I(Kr) of the guinea-pig cardiac delayed rectifier K(+) current is inhibited by beta(1)-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways.	2002 Feb 1	11827686
Neurohormonal activation in heart failure after acute myocardial infarction treated with beta-receptor antagonists.	2002 Jan	11812667
Adenylate cyclase activity in postmortem brain of suicide subjects: reduced response to beta-adrenergic stimulation.	2003 Dec 15	14675811
Pharmacological characterization of putative beta1-beta2-adrenergic receptor heterodimers.	2003 Feb	12710533
Partial agonist activity of bucindolol is dependent on the activation state of the human beta1-adrenergic receptor.	2003 Jul 22	12847069
Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1-adrenoceptor stimulation.	2004 Apr	15179140
Adrenergic regulation of vascular smooth muscle tone in calf digital artery.	2004 Aug	15305854
Agonist binding and activation of the rat beta(1)-adrenergic receptor: role of Trp(134(3.28)), Ser(190(4.57)) and Tyr(356(7.43)).	2004 Aug 15	15276075
Role of adenylate and guanylate cyclases in beta1-, beta2-, and beta3-adrenoceptor-mediated relaxation of internal anal sphincter smooth muscle.	2004 Mar	14711933
Dobutamine inhibits phorbol-myristate-acetate-induced activation of nuclear factor-kappaB in human T lymphocytes in vitro.	2004 Nov	15502056
Effect of overexpressed adenylyl cyclase VI on beta 1- and beta 2-adrenoceptor responses in adult rat ventricular myocytes.	2004 Oct	15381636
Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.	2004 Sep 15	15371517
A clinical, physiology and pharmacology evaluation of orthostatic hypotension in the elderly.	2005	16307360
In vitro evidence that carteolol is a nonconventional partial agonist of guinea pig cardiac beta1-adrenoceptors: a comparison with xamoterol.	2005 Dec	16160085
Sulfation in dog.	2005 Jun	15975044
Site of action of beta-ligands at the human beta1-adrenoceptor.	2005 Jun	15716385
PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning.	2005 Jun 1	15914118
Beta1-adrenergic receptors maintain fetal heart rate and survival.	2006	16210849
Functional beta-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes.	2006 Jul 1	16631628
NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells.	2006 Oct 1	16671086
Carvedilol in the treatment of chronic heart failure: lessons from the Carvedilol Or Metoprolol European Trial.	2007	17583173
Are we misunderstanding beta-blockers.	2007 Aug 9	17433471
Advanced-glycation end products (AGEs) derived from glycated albumin suppress early beta1-adrenergic preconditioning.	2007 Feb	17227443
Sympathetic neurotransmission modulates expression of inflammatory markers in the rat retina.	2007 Jan	17067575
beta(2) and beta(3)-adrenoceptor inhibition of alpha(1)-adrenoceptor-stimulated Ca(2+) elevation in human cultured prostatic stromal cells.	2007 Sep 10	17617401
The adrenergic receptor subtypes present in frog (Rana esculenta) skin.	2008 Aug	18544474
Maintenance of beta-adrenergic receptor signaling can reduce Fas signaling in human retinal endothelial cells.	2009 Oct	19523948
Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain.	2010 Jan	19840789

Patents

Sample Use Guides

In Vivo Use Guide

Xamoterol at 200 mg and 400 mg orally once daily had no effect on the mean resting heart rate but there was a small (5.7 beats min-1) but significant reduction in resting heart rate on 600 mg at 2-2.5 h after dosing. All three doses of xamoterol significantly reduced the maximum exercise heart rate at 2-2.5 h after dosing. Xamoterol at all three doses significantly increased exercise duration at 2-2.5 h after dosing but not at 24 h.

Route of Administration: Oral

In Vitro Use Guide

human microvascular retinal endothelial cells (HMREC) cultured in high (25 mM) and low glucose (5 mM) conditions were serum starved for 18-24 h, followed by treatment with a beta-1-adrenergic receptor agonist, xamoterol (10 microM), for 15, 30, and 45 min.

Name

Type

Language

XAMOTEROL FUMARATE

Official Name

English

XAMOTEROL FUMARATE [USAN]

Common Name

English

ICI-118,587 HEMIFUMARATE

Common Name

English

ICI-118587 HEMIFUMARATE

Common Name

English

Xamoterol fumarate [WHO-DD]

Common Name

English

4-MORPHINOLINECARBOXAMIDE, N-*(2-((2-HYDROXY-3-(4-HYDROXYPHENOXY)PROPYL)AMINO)ETHYL)-, (±)-, (E)-2-BUTENEDIOATE (2:1) (SALT)

Common Name

English

XAMOTEROL HEMIFUMARATE [MI]

Common Name

English

XAMOTEROL FUMARATE [MART.]

Common Name

English

(±)-N-(2-((2-HYDROXY-3-(P-HYDROXYPHENOXY)PROPYL)AMINO)ETHYL)-4-MORPHOLINECARBOXAMIDE FUMARATE (2:1) (SALT)

Common Name

English

XAMOTEROL FUMARATE [JAN]

Common Name

English

ICI 118,587

Code

English

XAMOTEROL HEMIFUMARATE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C78322