XAMOTEROL

Possibly Marketed Outside US

Details

Stereochemistry	RACEMIC
Molecular Formula	C16H25N3O5
Molecular Weight	339.3868
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(CNCCNC(=O)N1CCOCC1)COC2=CC=C(O)C=C2

InChI

InChIKey=DXPOSRCHIDYWHW-UHFFFAOYSA-N

InChI=1S/C16H25N3O5/c20-13-1-3-15(4-2-13)24-12-14(21)11-17-5-6-18-16(22)19-7-9-23-10-8-19/h1-4,14,17,20-21H,5-12H2,(H,18,22)

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 163 Target ID: CHEMBL213 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6128041 \| https://www.ncbi.nlm.nih.gov/pubmed/2862938	Partial Agonist 297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Heart failure 106 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 8583	CORWIN Approved Use Xamoterol (Fumarate) is primarily indicated in conditions like Heart failure.

C_max

Value	Dose	Co-administered	Analyte	Population
27.6 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
146 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Analyte	Population
1054 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	14 mg single, intravenous dose: 14 mg route of administration: Intravenous experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
168 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
711 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Analyte	Population
7.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	14 mg single, intravenous dose: 14 mg route of administration: Intravenous experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
15.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
16.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
97% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
97% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2904884/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		XAMOTEROL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

Doses

Dose	Population	Adverse events
300 mg 2 times / day multiple, oral Highest studied dose Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/2139340/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/2139340/	Sources: https://pubmed.ncbi.nlm.nih.gov/2139340/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP4 290 MRP3 246 CYP19A1 429 MRP2 499 BSEP 550	OCT2 434 OCT1 393 P-gp 2052

Drug as perpetrator

Target	Modality	Activity
BSEP 554	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw2MDIwIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	no [IC50 >133 uM]
MRP2 625	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1NzQ4IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	no [IC50 >133 uM]
MRP3 326	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1OTE4IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	no [IC50 >133 uM]
MRP4 345	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwxNzQzMTI4IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	no [IC50 >133 uM]
CYP19A1 430	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/155774#section=BioAssay-Results Page: 56.0	no

Drug as victim

Target	Modality	Activity
P-gp 2052	substrate 4014 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/155774#section=BioAssay-Results Page: 59.0	no
OCT1 393	substrate 4014 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1Njg1IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	yes
OCT2 434	substrate 4014 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwxNzQzMTIyIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDc1NzUzIn19	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/155774#section=BioAssay-Results Page: 31.0

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
Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers.	1999 Jan	10073741
Binding pockets of the beta(1)- and beta(2)-adrenergic receptors for subtype-selective agonists.	1999 Nov	10531390
Cardioselective beta-blocker use in patients with reversible airway disease.	2001	11406056
The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure.	2001 Aug	11532543
Beta2-adrenoceptor-mediated prejunctional facilitation and postjunctional inhibition of sympathetic neuroeffector transmission in the guinea pig vas deferens.	2001 Aug	11454924
Constitutive activity of the human beta(1)-adrenergic receptor in beta(1)-receptor transgenic mice.	2001 Oct	11562432
beta-Adrenergic receptors, transgenic mice, and pharmacological model systems.	2001 Oct	11562422
Cardioselective beta-blockers for reversible airway disease.	2002	11869646
Characterization of beta-adrenoceptor subtype in bladder smooth muscle in cynomolgus monkey.	2002 Jan	11855669
Neurohormonal activation in heart failure after acute myocardial infarction treated with beta-receptor antagonists.	2002 Jan	11812667
Bucindolol displays intrinsic sympathomimetic activity in human myocardium.	2002 May 21	12021232
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
Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation.	2003 Jun 6	12670949
Functional and molecular characterization of beta-adrenoceptors in the internal anal sphincter.	2003 May	12606629
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
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
Functional beta-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes.	2006 Jul 1	16631628
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
Understanding cardiac output.	2008	18771592
Carvedilol in the treatment of elderly patients with chronic heart failure.	2008	18488879
The adrenergic receptor subtypes present in frog (Rana esculenta) skin.	2008 Aug	18544474
Beta-adrenergic receptor stimulation modulates iNOS protein levels through p38 and ERK1/2 signaling in human retinal endothelial cells.	2008 Jul	18541234
Effect of inhibition of extracellular signal-regulated kinase on relaxations to beta-adrenoceptor agonists in porcine isolated blood vessels.	2009 Dec	19912229
Four close bupranolol analogues are antagonists at the low-affinity state of beta1-adrenoceptors.	2009 Mar	19439807
Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.	2009 Nov 18	20368182
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
The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation.	2010 Jun	20354155
Beta-blockers and heart failure.	2010 Mar-Apr	21180298
A full pharmacological analysis of the three turkey β-adrenoceptors and comparison with the human β-adrenoceptors.	2010 Nov 30	21152092

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

Official Name

English

ICI-118,587

Preferred Name

English

4-MORPHOLINECARBOXAMIDE, N-(2-((2-HYDROXY-3-(4-HYDROXYPHENOXY)PROPYL)AMINO)ETHYL)-, (±)-

Systematic Name

English

XAMOTEROL [USAN]

Common Name

English

ICI-118587

Code

English

XAMOTEROL [MI]

Common Name

English

(±)-N-(2-((2-HYDROXY-3-(P-HYDROXYPHENOXY)PROPYL)AMINO)ETHYL)-4-MORPHOLINECARBOXAMIDE

Common Name

English

xamoterol [INN]

Common Name

English

Xamoterol [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C48149