timolol (PD002871, BLJRIMJGRPQVNF-JTQLQIEISA-N)

General

Preferred name

timolol

Synonyms

S(-)-Timolol maleate

(S)-Timolol maleate

MK 950

L-714,465 (Maleate)

TIMOLOL MALEATE

Timolol maleate salt

MK 950(S)-Timolol Maleate

TIMOLOL ANHYDROUS

(S)-L-714,465 (maleate)

(S)-Timolol (Maleate)

MK-950,(S)-Timolol Maleate

WP-934

Istalol

Timolol hydrogen maleate salt

Timolol (as maleate)

Aquanil

Timoptic Xe

Timoptic In Ocudose

BLOCADREN

Ophtamolol

Timololi maleas

NSC-757351

Timoptic

Timoptic-XE

Timolol maleate, s-enantiomer

TIMOLOL HEMIHYDRATE

GLAUCOL

BETIMOL

GLAU-OPT

TIOPEX

BETIM

NYOGEL

Timolol (maleate)

P&D ID

PD002871

CAS

26921-17-5

60469-65-0

131628-37-0

26839-75-8

Tags

available

drug

Approved by

FDA

PMDA

First approval

1978

Drug indication

High blood pressure

Anti-Adrenergic (beta-receptor)

Drug Status

approved

Max Phase

4.0

Structure

PD002871

timolol

approved

RO5

316.16

HBA

HBD

LOGP

0.5

Structure formats

SMILES

CC(C)(C)NC[C@H](O)COc1nsnc1N1CCOCC1

InChI

InChI=1S/C13H24N4O3S/c1-13(2,3)14-8-10(18)9-20-12-11(15-21-16-12)17-4-6-19-7-5-17/h10,14,18H,4-9H2,1-3H3/t10-/m0/s1

InChIkey

BLJRIMJGRPQVNF-JTQLQIEISA-N

MOL

timolol RDKit 2D 21 22 0 0 0 0 0 0 0 0999 V2000 -6.3289 -8.7202 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.9023 -9.1838 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4758 -9.6473 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.3659 -10.6103 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.4388 -7.7572 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.9716 -7.4453 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.5081 -6.0187 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5118 -4.9040 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.0409 -5.7068 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.5773 -4.2803 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 0.8899 -3.9684 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 2.0046 -4.9721 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 3.3037 -4.2221 0.0000 S 0 0 0 0 0 0 0 0 0 0 0 0 2.9918 -2.7549 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 1.5000 -2.5981 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.7500 -1.2990 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 1.5000 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.7500 1.2990 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7500 1.2990 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.5000 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7500 -1.2990 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 2 3 1 0 2 4 1 0 2 5 1 0 5 6 1 0 6 7 1 0 7 8 1 6 7 9 1 0 9 10 1 0 10 11 1 0 11 12 2 0 12 13 1 0 13 14 1 0 14 15 2 0 15 16 1 0 16 17 1 0 17 18 1 0 18 19 1 0 19 20 1 0 20 21 1 0 15 11 1 0 21 16 1 0 M END > <ID> PD002871 > <Name> timolol

Description

(extracted from source data)

PHARMACODYNAMICS Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.[A179506,A179509,A179512,L6727]. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses.[L6757]; ;

MOA Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate.[A179521] Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure.[A179524,A179527] In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure.[L6724,L6727,L6733]; ; The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye.[L6730] According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis.[A179515]

INDICATION Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure.[L6724,L6727] In certain cases, timolol is used in the prevention of migraine headaches.[A179530,L6742]

ROE Timolol and its metabolites are mainly found excreted in the urine.[A179560]

TOXICITY The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse.[MSDS]; ; Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment.[L6724]

METABOLISM Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19.[A179551,L6724] 15-20% of a dose undergoes first-pass metabolism.[A179560] Despite its relatively low first pass metabolism, timolol is 90% metabolized.[A179560] Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant.[A179551]

ABSORPTION The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 Â± 24.5% [A179539], indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers.[A179548]; ; The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.[A179539]

HALF-LIFE Timolol half-life was measured at 2.9 Â± 0.3 h hours in a clinical study of healthy volunteers.[A179560]

DESCRIPTION Marketed formulations may contain timolol maleate (PubChem CID 5281056). (GtoPdb)

DESCRIPTION Selective H1 inverse agonist (Tocris Bioactive Compound Library)

DESCRIPTION beta Adrenoceptor antagonist; antihypertensive; antiarrhythmic; antiglaucoma agent (LOPAC library)

DESCRIPTION β1 antagonist (Tocriscreen Total)

Protein targets

9.7

9.68

ADRB2 Beta-2 adrenergic receptor antagonist

BIOCHEM 11.2x

CELL-BASED 12.3x

9.44

ADRB1 Beta-1 adrenergic receptor

8.65

8.59

ADRB1 Beta-1 adrenergic receptor antagonist

6.41

SIGMAR1 Sigma non-opioid intracellular receptor 1

6.4

ADRB3 Beta-3 adrenergic receptor

6.21

5.38

HTR1A 5-hydroxytryptamine receptor 1A

5.55

AMPC Beta-lactamase

5.3

CHRM1 Muscarinic acetylcholine receptor M1

5.28

DRD1 D(1A) dopamine receptor

NFKB1 Nuclear factor NF-kappa-B p105 subunit

4.9

CYP2D6 Cytochrome P450 2D6

4.7

CYP3A4 Cytochrome P450 3A4

4.5

CYP1A2 Cytochrome P450 1A2

Target pathways

Activation of NF-kappaB in B cells

R-HSA-1169091

NFKB1

Adrenoceptors

R-HSA-390696

ADRB3

ADRB2

ADRB1

Aflatoxin activation and detoxification

R-HSA-5423646

CYP1A2

CYP3A4

Aromatic amines can be N-hydroxylated or N-dealkylated by CYP1A2

R-HSA-211957

CYP1A2

Aspirin ADME

R-HSA-9749641

CYP3A4

CYP2D6

Atorvastatin ADME

R-HSA-9754706

CYP3A4

Biosynthesis of maresin-like SPMs

R-HSA-9027307

CYP1A2

CYP3A4

CYP2D6

Biosynthesis of protectins

R-HSA-9018681

CYP1A2

Cargo recognition for clathrin-mediated endocytosis

R-HSA-8856825

ADRB2

CD209 (DC-SIGN) signaling

R-HSA-5621575

NFKB1

Clathrin-mediated endocytosis

R-HSA-8856828

ADRB2

CLEC7A (Dectin-1) signaling

R-HSA-5607764

NFKB1

CLEC7A/inflammasome pathway

R-HSA-5660668

NFKB1

CYP2E1 reactions

R-HSA-211999

CYP2D6

DEx/H-box helicases activate type I IFN and inflammatory cytokines production

R-HSA-3134963

NFKB1

Dopamine receptors

R-HSA-390651

DRD1

Downstream TCR signaling

R-HSA-202424

NFKB1

Fatty acids

R-HSA-211935

CYP2D6

FCERI mediated NF-kB activation

R-HSA-2871837

NFKB1

G alpha (q) signalling events

R-HSA-416476

CHRM1

G alpha (s) signalling events

R-HSA-418555

ADRB3

ADRB2

DRD1

ADRB1

HCMV Early Events

R-HSA-9609690

NFKB1

IkBA variant leads to EDA-ID

R-HSA-5603029

NFKB1

Interleukin-1 processing

R-HSA-448706

NFKB1

Interleukin-1 signaling

R-HSA-9020702

NFKB1

MAP3K8 (TPL2)-dependent MAPK1/3 activation

R-HSA-5684264

NFKB1

Methylation

R-HSA-156581

CYP1A2

Miscellaneous substrates

R-HSA-211958

CYP2D6

Muscarinic acetylcholine receptors

R-HSA-390648

CHRM1

Neutrophil degranulation

R-HSA-6798695

NFKB1

NF-kB is activated and signals survival

R-HSA-209560

NFKB1

Phase I - Functionalization of compounds

R-HSA-211945

CYP3A4

PKMTs methylate histone lysines

R-HSA-3214841

NFKB1

Potential therapeutics for SARS

R-HSA-9679191

SIGMAR1

Prednisone ADME

R-HSA-9757110

CYP3A4

Purinergic signaling in leishmaniasis infection

R-HSA-9660826

NFKB1

Regulated proteolysis of p75NTR

R-HSA-193692

NFKB1

Regulation of NFE2L2 gene expression

R-HSA-9818749

NFKB1

RIP-mediated NFkB activation via ZBP1

R-HSA-1810476

NFKB1

SARS-CoV-1 activates/modulates innate immune responses

R-HSA-9692916

NFKB1

Senescence-Associated Secretory Phenotype (SASP)

R-HSA-2559582

NFKB1

Serotonin receptors

R-HSA-390666

HTR1A

Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)

R-HSA-2142816

CYP1A2

Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)

R-HSA-2142670

CYP1A2

TAK1-dependent IKK and NF-kappa-B activation

R-HSA-445989

NFKB1

The NLRP3 inflammasome

R-HSA-844456

NFKB1

TRAF6 mediated NF-kB activation

R-HSA-933542

NFKB1

Transcriptional Regulation by VENTX

R-HSA-8853884

NFKB1

Transcriptional regulation of white adipocyte differentiation

R-HSA-381340

NFKB1

Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells

R-HSA-9860927

NFKB1

Ub-specific processing proteases

R-HSA-5689880

ADRB2

Xenobiotics

R-HSA-211981

CYP3A4

CYP2D6

References

EUbOPEN Chemogenomics Library - PDSP Primary Binding (dataset)

EUbOPEN Chemogenomics Library - PDSP Secondary Binding (dataset)

EUbOPEN Chemogenomics Library - GPCR Dose-Respose (dataset)

2023 A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.

Sutherland JJ, Yonchev D et al. Nat Commun

Screening of ~5500 FDA-approved drugs and clinical candidates for anti-SARS-CoV-2 activity (dataset)

2020 Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents.

Chang Q, Long J et al. Bioorg Med Chem

2018 Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy.

Nocentini A, Ceruso M et al. J Med Chem

2013 A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development.

Morgan RE, van Staden CJ et al. Toxicol Sci

2010 Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.

Morgan RE, Trauner M et al. Toxicol Sci

2009 Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.

Yuan J, Johnson RL et al. Nat. Chem. Biol.

2006 Role of Tyr(356(7.43)) and Ser(190(4.57)) in antagonist binding in the rat beta1-adrenergic receptor.

Rezmann-Vitti LA, Nero TL et al. J. Med. Chem.

2005 The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors.

Baker JG Br J Pharmacol

2005 A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series.

Vaz RJ; Nayeem A et al.

2004 Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers.

Joseph SS, Lynham JA et al. Naunyn Schmiedebergs Arch Pharmacol

2003 Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling.

Baker JG, Hall IP et al. Mol Pharmacol

1996 Binding of arylpiperazines, (aryloxy)propanolamines, and tetrahydropyridylindoles to the 5-HT1A receptor: contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-affinity relationship models.

Gaillard P, Carrupt PA et al. J. Med. Chem.

1986 Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy]phenyl]imidazole class. 2.

Baldwin JJ, Christy ME et al. J. Med. Chem.

1983 Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazole class.

Baldwin JJ, Denny GH et al. J. Med. Chem.

1982 Use of (S)-(trifloxymethyl)oxirane in the synthesis of a chiral beta-adrenoceptor antagonist, (R)- and (S)-9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene.

Baldwin JJ, McClure DE et al. J. Med. Chem.

PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors and Activators of N370S glucocerebrosidase as a Potential Chaperone Treatment of Gaucher Disease: Purified N370S Glucocerebrosidase. (Class of assay: confirmatory) [Related pubchem assays: 2101 ] AID 2597

DrugMatrix in vitro pharmacology data (dataset)