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Also known as: 59803-98-4, Bromoxidine, Uk 14,304, 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)quinoxalin-6-amine, 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)-6-quinoxalinamine, 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline
Molecular Formula
C11H10BrN5
Molecular Weight
292.13  g/mol
InChI Key
XYLJNLCSTIOKRM-UHFFFAOYSA-N
FDA UNII
E6GNX3HHTE

CAS 59803-98-4
A quinoxaline derivative and ADRENERGIC ALHPA-2 RECEPTOR AGONIST that is used to manage INTRAOCULAR PRESSURE associated with OPEN-ANGLE GLAUCOMA and OCULAR HYPERTENSION.
Brimonidine is an alpha-Adrenergic Agonist. The mechanism of action of brimonidine is as an Adrenergic alpha-Agonist.
1 2D Structure

CAS 59803-98-4

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine
2.1.2 InChI
InChI=1S/C11H10BrN5/c12-9-7(17-11-15-5-6-16-11)1-2-8-10(9)14-4-3-13-8/h1-4H,5-6H2,(H2,15,16,17)
2.1.3 InChI Key
XYLJNLCSTIOKRM-UHFFFAOYSA-N
2.1.4 Canonical SMILES
C1CN=C(N1)NC2=C(C3=NC=CN=C3C=C2)Br
2.2 Other Identifiers
2.2.1 UNII
E6GNX3HHTE
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate

2. 5-bromo-6-(imidazolidinylideneamino)quinoxaline

3. 5-bromo-6-(imidazolin-2-ylamino)quinoxaline

4. Agn 190342

5. Agn-190342

6. Agn190342

7. Alphagan

8. Alphagan P

9. Brimonidine Purite

10. Brimonidine Tartrate

11. Brimonidine Tartrate (1:1)

12. Brimonidine Tartrate (1:1), (s-(r*,r*))-isomer

13. Brimonidine Tartrate, (r-(r*,r*))-isomer

14. Bromoxidine

15. Mirvaso

16. Ratio Brimonidine

17. Ratio-brimonidine

18. Sanrosa

19. Uk 14,304

20. Uk 14,304 18

21. Uk 14,304-18

22. Uk 14,30418

23. Uk 14,308

24. Uk 14304

25. Uk 14308

26. Uk-14,304-18

27. Uk-14,308

28. Uk-14304

29. Uk14,30418

30. Uk14,308

31. Uk14304

2.3.2 Depositor-Supplied Synonyms

1. 59803-98-4

2. Bromoxidine

3. Uk 14,304

4. 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)quinoxalin-6-amine

5. 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)-6-quinoxalinamine

6. 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline

7. Uk-14304

8. 5-bromo-6-(imidazolin-2-ylamino)quinoxaline

9. Agn 190342

10. 6-quinoxalinamine, 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)-

11. Uk 14304

12. Agn-190342

13. Mls000069370

14. E6gnx3hhte

15. Mfcd00153878

16. Chembl844

17. Nsc-318825

18. Smr000058355

19. Chebi:3175

20. Agn-190342 Free Base

21. Brimonidine (inn)

22. Uk-1430418 Free Base

23. Ncgc00016069-09

24. Uk 14304;agn190342

25. Brimonidine [inn]

26. Dsstox_cid_25221

27. Dsstox_rid_80758

28. Dsstox_gsid_45221

29. Uk 14304 (tartrate);agn190342 (tartrate)

30. Brimonidinum

31. Brimonidine [inn:ban]

32. [3h]brimonidine

33. Cas-59803-98-4

34. N-(5-bromoquinoxalin-6-yl)imidazolidin-2-imine

35. Sr-01000000023

36. Unii-e6gnx3hhte

37. Brimonidina

38. Brn 0751629

39. Lk 14304-18

40. Agn190342

41. Uk14304

42. Tocris-0425

43. [3h]-uk14304

44. Opera_id_612

45. Lopac-u-104

46. Brimonidine [mi]

47. Brimonidine [vandf]

48. Cid_2435

49. Lopac0_001216

50. Schembl24670

51. Brimonidine [who-dd]

52. Gtpl520

53. 5-bromo-n-(2-imidazolin-2-yl)-6-quinoxalinamine

54. Mls001076349

55. Bidd:gt0649

56. Gtpl5386

57. Dtxsid3045221

58. Bdbm34572

59. 5-bromo-n-(4,5-dihydro-2-imidazolyl)quinoxalin-6-amine

60. Hms3259p09

61. Hms3263d14

62. Hms3266o03

63. Hms3411k05

64. Hms3675k05

65. Hms3887k07

66. Amy22318

67. Bcp12632

68. Ex-a5415

69. Hy-b0659

70. Tox21_110299

71. Tox21_501216

72. Ac-162

73. Nsc318825

74. Pdsp1_000640

75. Pdsp2_000635

76. S9508

77. Zinc21303210

78. Akos005267239

79. Tox21_110299_1

80. Ccg-205290

81. Db00484

82. Gs-3236

83. Lp01216

84. Nc00638

85. Nsc 318825

86. Sdccgsbi-0051183.p002

87. Mrf-0000657

88. Ncgc00016069-01

89. Ncgc00016069-02

90. Ncgc00016069-03

91. Ncgc00016069-04

92. Ncgc00016069-05

93. Ncgc00016069-06

94. Ncgc00016069-07

95. Ncgc00016069-08

96. Ncgc00016069-10

97. Ncgc00016069-11

98. Ncgc00016069-12

99. Ncgc00016069-13

100. Ncgc00016069-24

101. Ncgc00023468-02

102. Ncgc00023468-04

103. Ncgc00023468-05

104. Ncgc00023468-06

105. Ncgc00023468-07

106. Ncgc00261901-01

107. Sy053060

108. Uk14,304

109. Brimonidine 100 Microg/ml In Acetonitrile

110. B4132

111. Eu-0101216

112. Ft-0630717

113. Ft-0650586

114. En300-50880

115. Uk 14304-18

116. C07886

117. C75796

118. D07540

119. 5-bromo-6-(2-imidazolidinylidenamino)quinoxaline

120. 5-bromo-6-(2-imidazolin-2-ylamino) Quinoxaline

121. 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline

122. 6-quinoxalinamine,5-dihydro-1h-imidazol-2-yl)-

123. 803b984

124. A832477

125. L000615

126. Q577377

127. Sr-01000000023-2

128. Sr-01000000023-4

129. Brd-k68264559-001-10-0

130. Z802671510

131. (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1h-imidazol-2-yl)-amine

132. 5-bromanyl-n-(4,5-dihydro-1h-imidazol-2-yl)quinoxalin-6-amine

133. 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate (1:1).

134. 6-quinoxalinamine, 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)- (9ci)

135. 6-quinoxalinamine, 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)-, (s-(r*,r*))-2,3-dihydroxybutanedioate (1:1)

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 292.13 g/mol
Molecular Formula C11H10BrN5
XLogP30.6
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count3
Rotatable Bond Count2
Exact Mass291.01196 g/mol
Monoisotopic Mass291.01196 g/mol
Topological Polar Surface Area62.2 Ų
Heavy Atom Count17
Formal Charge0
Complexity308
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

**Opthalmic** Indicated for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension as monotherapy or combination product with [brinzolamide]. **Topical** Indicated for the treatment of persistent (non-transient) facial erythema of rosacea in adults 18 years of age or older.


FDA Label


Treatment of conjunctival hyperaemia


5 Pharmacology and Biochemistry
5.1 Pharmacology

Brimonidine is a highly selective alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha1-adrenergic receptor. This characteristic gives the drug some therapeutic advantages, since it reduces the risk of systemic side effects, such as systemic hypotension, bradycardia, and sedation. In addition, there is a reduction in the risk for developing alpha-1 mediated ocular unwanted effects, such as conjunctival blanching, mydriasis, and eyelid retraction. However, despite high alpha-2 receptor specificity, brimonidine may still produce alpha-1 adrenoceptor-mediated ocular effects, such as conjunctival vasoconstriction. Brimonidine has a peak ocular hypotensive effect occurring at two hours post-dosing. In a randomized, double-blind clinical study, ocular administration of 0.2% brimonidine in healthy volunteers resulted in a 23% reduction of mean intraocular pressure from baseline at 3 hours following administration. In comparative studies consisting of patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive effect of brimonidine was maintained during treatment periods of up to 1 year. Brimonidine mediates vasoconstrictive effects and it was shown to exhibit anti-inflammatory properties in _ex vivo_ human skin model and _in vivo_ inflammation models. In a clinial trials consisting of adults with moderate to severe facial erythema of rosacea, brimonidine was shown to improve the extent of redness at 3 hours after application, compared to placebo. It was shown to be a potent vasoconstrictor of human subcutaneous vessels with a diameter of less than 200 m. In _in vivo_ mouse inflammation models, brimonidine displayed anti-inflammatory properties by inhibiting edema. In a randomized, double-blind study, brimonidine reduced erythema for the 12 hours of the study in a dose-dependent manner. When adminsitered systemically, brimonidine was shown to cause cardiovascular effects by decreasing blood pressure, decreasing heart and respiratory rate, and prolonging the PR interval in the electrocardiogram. This is due to the targeting of adrenoceptors by the drug. Although the clinical significance has not been established, there is evidence that brimonidine exhibits neuroprotective activity in experimental models of cerebral ischemia and optic nerve injury. _In vitro_ studies show that brimonidine mediated protective effects on neuronal cells from kainate acid insult and on cultured retinal ganglion cells from glutamate-induced cytotoxicity, which is a possible mediator of secondary neuronal degeneration in human glaucoma. Neuroprotective actions of brimonidine were also demonstrated in rat models of acute retinal ischemia and chronic IOP elevation. It has been proposed that brimonidine may exert neuroprotective effects on the retina and optic nerve by enhancing intrinsic retinal ganglion cell survival mechanisms and/or induction of neuronal survival factors, such as bFGF. However, further investigations are needed to conclude on these possible therapeutic benefits of the drug.


5.2 MeSH Pharmacological Classification

Antihypertensive Agents

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)


Adrenergic alpha-2 Receptor Agonists

Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
BRIMONIDINE
5.3.2 FDA UNII
E6GNX3HHTE
5.3.3 Pharmacological Classes
Established Pharmacologic Class [EPC] - alpha-Adrenergic Agonist
5.4 ATC Code

S01EA05

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


D - Dermatologicals

D11 - Other dermatological preparations

D11A - Other dermatological preparations

D11AX - Other dermatologicals

D11AX21 - Brimonidine


S - Sensory organs

S01 - Ophthalmologicals

S01E - Antiglaucoma preparations and miotics

S01EA - Sympathomimetics in glaucoma therapy

S01EA05 - Brimonidine


S - Sensory organs

S01 - Ophthalmologicals

S01G - Decongestants and antiallergics

S01GA - Sympathomimetics used as decongestants

S01GA07 - Brimonidine


5.5 Absorption, Distribution and Excretion

Absorption

Brimonidine readily penetrates the cornea following ocular administration to reach pharmacologically active concentrations in the aqueous humor and ciliary body, the putative sites of its IOP-lowering activity. Following ocular administration of 0.2% brimonidine solution, the peak plasma concentrations were achieved within 1 to 4 hours. In a clinical study of adult subjects with facial erythema of rosacea, brimonidine was cutaneously applied on facial skin in a repeated manner. While there was no drug accumulation in plasma, the highest peak plasma concentrations (Cmax) and AUC were 46 62 pg/mL and 417 264 pgxhr/mL, respectively.


Route of Elimination

Brimonidine and its metabolites are predominantly eliminated via urinary excretion, with 74% of the total dose being found in the urine.


Volume of Distribution

The volume of distribution of brimonidine has not been established. In animal studies, brimonidine was shown to cross the placenta and enter into the fetal circulation to a limited extent. As its lipophilicity is relatively low, brimonidine is not reported to easily cross the blood-brain barrier.


Clearance

The apparent clearance has not been studied. However, the systemic clearance of brimonidine is reported to be rapid. Approximately 87% of the total radioactive dose of brimonidine was shown to be eliminated within 120 hours following oral administration.


5.6 Metabolism/Metabolites

Brimonidine is reported to be metabolized in the cornea. Brominidine that reaches the systemic circulation upon topical administration undergoes extensive hepatic metabolism mediated by hepatic aldehyde oxidases.


5.7 Biological Half-Life

Following ocular administration of 0.2% brimonidine solution, the systemic half-life was approximately 3 hours.


5.8 Mechanism of Action

In the eye, alpha-1 adrenoceptors play a role in vasoconstriction, mydriasis, eyelid retraction, and elevation of intraocular pressure (IOP) whereas alpha-2 adrenoceptors are responsible for IOP reduction via a complex Gi-coupled signaling cascade pathway. Activation of alpha-2 receptors leads to inhibition of adenylyl cyclase and reduction of cyclic AMP levels. As a result, there is a decrease in norpinephrine (NE) release at the synaptic junction, NE-induced stimulation of beta-2 adrenoceptors, and production of aqueous humor by the ciliary epithelium. An elevated IOP is the most significant risk factor for developing glaucomatous optic neuropathy, which is associated with progressive visual field loss and functional disability if left untreated. Regardless of the etiology of the disease, the aim of current therapies for glaucoma is to reduce IOP, as reduction of IOP significantly reduces the risk of progression of vision loss even when IOP is already within the normal range. When administered ophthalmically, brimonidine is rapidly absorbed into the eye, acts as an agonist at ocular alpha-2 adrenoceptors and lowers IOP via a dual mechanism of action. It is proposed that initial dosing of the drug causes a reduction in aqueous humour production and chronic dosing leads to an increase in uveoscleral outflow. Brimonidine does not affect episcleral venous pressure. By reducing IOP, brimonidine aims to reduce the likelihood of glaucomatous visual field loss in ocular hypertension, and slow the progression of visual field defect in established open-angle glaucoma. When applied topically on skin, brimonidine reduces erythema through direct vasocontriction of small arteries and veins. As brimonidine mediates a potent peripheral vasoconstrictive activity by selectively working on the alpha-2 adrenoceptors, the use of brimonidine is thought to be efficacious for the treatment of facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature of the face.


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