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CAS-114798-26-4

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Also known as: 114798-26-4, Dup 89, Allisartan, Lortaan, Cozaar, Hyzaar

Molecular Formula

C₂₂H₂₃ClN₆O

Molecular Weight

422.9 g/mol

InChI Key

PSIFNNKUMBGKDQ-UHFFFAOYSA-N

FDA UNII

JMS50MPO89

An antagonist of ANGIOTENSIN TYPE 1 RECEPTOR with antihypertensive activity due to the reduced pressor effect of ANGIOTENSIN II.

Losartan is an Angiotensin 2 Receptor Blocker. The mechanism of action of losartan is as an Angiotensin 2 Receptor Antagonist.

1 2D Structure

CAS 114798-26-4

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

2.1.2 InChI

InChI=1S/C22H23ClN6O/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22/h4-7,9-12,30H,2-3,8,13-14H2,1H3,(H,25,26,27,28)

2.1.3 InChI Key

PSIFNNKUMBGKDQ-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CCCCC1=NC(=C(N1CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)CO)Cl

2.2 Other Identifiers

2.2.1 UNII

JMS50MPO89

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 2-butyl-4-chloro-1-((2'-(1h-etrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl)-1h-imidazole-5-methanol

2. Cozaar

3. Dup 753

4. Dup-753

5. Dup753

6. Losartan Monopotassium Salt

7. Losartan Potassium

8. Mk 954

9. Mk-954

10. Mk954

11. Monopotassium Salt, Losartan

12. Potassium, Losartan

13. Salt, Losartan Monopotassium

2.3.2 Depositor-Supplied Synonyms

1. 114798-26-4

2. Dup 89

3. Allisartan

4. Lortaan

5. Cozaar

6. Hyzaar

7. Losartan Potassium

8. Angizaar

9. Losartic

10. Lozap

11. Dup-753

12. Losartan (inn)

13. Chebi:6541

14. Dup-89

15. Mk-954

16. Nsc-758699

17. Jms50mpo89

18. (2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1h-imidazol-5-yl)methanol

19. [2-butyl-5-chloro-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

20. 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole

21. Dtxsid7023227

22. Hgp1405

23. Hgp-1405

24. 2-butyl-4-chloro-1-((2'-(1h-etrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl)-1h-imidazole-5-methanol

25. (1-((2'-(1h-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

26. (1-((2'-(2h-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

27. Ncgc00095125-01

28. Losartan [inn]

29. Losartan [inn:ban]

30. Dsstox_cid_3227

31. Dsstox_rid_76933

32. Dsstox_gsid_23227

33. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-((2'-(1h-tetrazol-5-yl)(1,1'- Biphenyl)-4-yl)methyl)-

34. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(2h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-

35. (1-((2'-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

36. [3h]losartan

37. Losartic (tn)

38. [2-butyl-5-chloranyl-3-[[4-[2-(2h-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

39. 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1h-imidazole-5-methanol

40. [3h]-losartan

41. Cas-114798-26-4

42. Sr-01000763170

43. Unii-jms50mpo89

44. Lorastan

45. [2-butyl-5-chloro-3-[[4-[2-(1h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

46. Mfcd00865831

47. Dup89

48. Spectrum_001713

49. Losartan [mi]

50. Schembl60

51. Losartan [vandf]

52. Spectrum2_001677

53. Spectrum3_000998

54. Spectrum4_001126

55. Spectrum5_001466

56. Epitope Id:140137

57. Losartan [who-dd]

58. Ec 601-329-8

59. Oprea1_644635

60. Us9624243, Losartin

61. Bspbio_002695

62. Gtpl590

63. Kbiogr_001611

64. Kbioss_002193

65. (2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl}-1h-imidazol-5-yl)methanol

66. Bidd:gt0286

67. Spectrum1504268

68. Spbio_001893

69. Gtpl3941

70. Bdbm82258

71. Hsdb 7043

72. Kbio2_002193

73. Kbio2_004761

74. Kbio2_007329

75. Kbio3_001915

76. Bcpp000183

77. Bdbm318822

78. Ex 89

79. Hms1922j13

80. Hms2093e22

81. Hms3715l11

82. Pharmakon1600-01504268

83. Bcp27731

84. Nsc_3961

85. Zinc3873160

86. Tox21_111435

87. Ccg-39095

88. Nsc758699

89. S5067

90. Stl419984

91. 2-butyl-4-chloro-1-[p-(o-1h-tetrazol-5ylphenyl)benzyl]imidazole-5-methanol

92. Akos015917390

93. Akos015994740

94. Tox21_111435_1

95. Ab07507

96. Bcp9000861

97. Db00678

98. Ks-5004

99. Nsc 758699

100. (2-butyl-4-chloro-1-{[2'-(2h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1h-imidazol-5-yl)methanol

101. 2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1h-tetrazol-5-yl)-biphenyl-4-yl]methyl]imidazole

102. Ncgc00095125-02

103. Ncgc00095125-03

104. Ncgc00095125-05

105. Ncgc00095125-08

106. Ncgc00095125-15

107. [2-butyl-4-chloro-1-({4-[2-(2h-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1h-imidazol-5-yl]methanol

108. 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-1h-imidazole-5-methanol

109. Bl164640

110. Hy-17512

111. Sbi-0206766.p001

112. Cas_114798-26-4

113. Ft-0631074

114. L0378

115. C07072

116. D08146

117. Ab01563296_01

118. 798l264

119. A803239

120. L000351

121. Q410074

122. Q-201321

123. Sr-01000763170-3

124. Sr-01000763170-4

125. Brd-k76205745-001-02-5

126. Brd-k76205745-001-04-1

127. F2173-0506

128. 2-butyl-4-chloro-1-(p-(o-1h-tetrazol-5-ylphenyl)benzyl)imidazole-5-methanol

129. 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole

130. 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole

131. (1-((2'-(2h-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

132. {2-butyl-5-chloro-3-[2'-(2h-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazol-4-yl}-methanol

133. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-((2'-(1h-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-

134. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- (9ci)

135. 2-butyl-4-chloro-1-[[2'-(2h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1h-imidazole-5-methanol

136. 2-butyl-4-chloro-1-[2'-(2h-tetrazol-5-yl)-1,1'-biphenyl-4-ylmethyl]-1h- Imidazole-5-methanol

137. 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole

2.4 Create Date

2005-03-25

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₂₃ClN₆O
Molecular Weight	422.9 g/mol
XLogP3	4.3
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	8
Exact Mass	422.1621871 g/mol
Monoisotopic Mass	422.1621871 g/mol
Topological Polar Surface Area	92.5 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	520
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Information

1 of 4
Drug Name	COZAAR
Active Ingredient	LOSARTAN POTASSIUM
Company	MERCK SHARP DOHME (Application Number: N020386)

2 of 4
Drug Name	LOSARTAN POTASSIUM
Active Ingredient	LOSARTAN POTASSIUM
Company	ALEMBIC PHARMS LTD (Application Number: A090428); AUROBINDO PHARMA (Application Number: A090083); CADISTA PHARMS (Application Number: A201170); HETERO LABS LTD V (Application Number: A203835); IPCA LABS LTD (Application Number: A200290); LUPIN LTD (Application Number: A078232); MACLEODS PHARMS LTD (Application Number: A202230); MYLAN (Application Number: A091590); PRINSTON INC (Application Number: A091497); SANDOZ (Application Number: A077424); TEVA (Application Number: A076958); TORRENT PHARMS (Application Number: A090467); UNICHEM LABS LTD (Application Number: A203030); UPSHER-SMITH LABS (Application Number: A090544); VIVA HLTHCARE (Application Number: A091541); VIVIMED GLOBAL (Application Number: A090382); WATSON LABS (Application Number: A091129); WEST-WARD PHARMS INT (Application Number: A077459); ZYDUS PHARMS USA INC (Application Number: A078243)

3 of 4
Drug Name	HYZAAR
Active Ingredient	HYDROCHLOROTHIAZIDE; LOSARTAN POTASSIUM
Company	MERCK SHARP DOHME (Application Number: N020387)

4 of 4
Drug Name	LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE
Active Ingredient	HYDROCHLOROTHIAZIDE; LOSARTAN POTASSIUM
Company	ALEMBIC PHARMS LTD (Application Number: A091617); AUROBINDO PHARMA (Application Number: A091629); CADISTA PHARMS (Application Number: A201845); IPCA LABS LTD (Application Number: A201682); LUPIN LTD (Application Number: A078245); MACLEODS PHARMS LTD (Application Number: A202289); MYLAN (Application Number: A091652); PRINSTON INC (Application Number: A204901); SANDOZ (Application Number: A077948); TEVA PHARMS (Application Number: A077157); TORRENT PHARMS (Application Number: A090528); UNICHEM LABS LTD (Application Number: A204832); WEST-WARD PHARMS INT (Application Number: A077732); ZYDUS PHARMS USA INC (Application Number: A078385)

4.2 Therapeutic Uses

Angiotensin II Type 1 Receptor Blockers; Anti-Arrhythmia Agents; Antihypertensive Agents

National Library of Medicine's Medical Subject Headings. Losartan. Online file (MeSH, 2014). Available from, as of September 2, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html

Cozarr is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics. /Included in US product label/

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0

Cozarr is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. /Included in US product label/

Cozaar is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio =300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Cozaar reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation). /Included in US product label/

For more Therapeutic Uses (Complete) data for Losartan (6 total), please visit the HSDB record page.

4.3 Drug Warning

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Cozaar as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Cozaar as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Cozaar, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Neonates with a history of in utero exposure to Cozaar If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./

For more Drug Warnings (Complete) data for Losartan (21 total), please visit the HSDB record page.

4.4 Drug Indication

Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage).

FDA Label

Proteinuria, Treatment of heart failure, Treatment of hypertension

5 Pharmacology and Biochemistry

5.1 Pharmacology

Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels.

5.2 MeSH Pharmacological Classification

Angiotensin II Type 1 Receptor Blockers

Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS. (See all compounds classified as Angiotensin II Type 1 Receptor Blockers.)

Anti-Arrhythmia Agents

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. (See all compounds classified as Anti-Arrhythmia Agents.)

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.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

LOSARTAN

5.3.2 FDA UNII

JMS50MPO89

5.3.3 Pharmacological Classes

Angiotensin 2 Receptor Blocker [EPC]; Angiotensin 2 Receptor Antagonists [MoA]

5.4 ATC Code

C09CA01

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

C - Cardiovascular system

C09 - Agents acting on the renin-angiotensin system

C09C - Angiotensin ii receptor blockers (arbs), plain

C09CA - Angiotensin ii receptor blockers (arbs), plain

C09CA01 - Losartan

5.5 Absorption, Distribution and Excretion

Absorption

Losartan is approximately 33% orally bioavailable. Losartan has a T_max of 1 hour and the active metabolite has a T_max of 3-4 hours. Taking losartan with food decreases the C_max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C_max of 200-250ng/mL.

Route of Elimination

A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.

Volume of Distribution

The volume of distribution of losartan is 34.417.9L and 10.31.1L for the active metabolite (E-3174).

Clearance

Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min.

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk.

Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).

Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses.

For more Absorption, Distribution and Excretion (Complete) data for Losartan (8 total), please visit the HSDB record page.

5.6 Metabolism/Metabolites

Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17.

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of (14)C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

Losartan has known human metabolites that include 2-[5-[2-[4-[[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-3-ium-3-yl]methyl]phenyl]phenyl]-1,5-dihydrotetrazol-2-yl]-6-(dihydroxymethyl)oxane-3,4,5-triol and Losartan carboxylic acid.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.7 Biological Half-Life

The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.

The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

5.8 Mechanism of Action

Losartan reversibly and competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with 1000 times more affinity than they bind to the AT₂ receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT₁ and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT₁ receptor and induce vasoconstriction, raising blood pressure.

Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist. /Salt not specified/

Goldberg MR et al; hepertension 25(1): 37-46 (1995)

IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro-athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiotensin II receptor antagonist widely used for the treatment of hypertension, diabetic nephropathy and congestive heart failure. In this study, we attempted to clarify whether losartan has an inhibitory effect on IL-1beta. To further elucidate the molecular mechanism underlying the anti-IL-1beta property of losartan, we studied the LPS+ATP-induced activation of NALP3 inflammasome which controls the muturation and secretion of IL-1beta. LPS and ATP were used to stimulate the release of IL-1beta from thioglycollate-elicited macrophages from BALB/c mice. The production of IL-1beta was evaluated by ELISA assay and NALP3, caspase-1, IL-beta mRNA levels were determined by reverse transcription-polymerase chain reaction. In cultured thioglycollate-elicited macrophages, we observed that LPS + ATP greatly enhanced IL-1 beta secretion (6938.00 +/- 83.45; P < 0.05) and the mRNA levels of NALP3, caspase-1 which are two main components of NALP3 inflammasome (60.88 +/- 8.28; 1.31 +/- 0.04, P < 0.05 for both). The macrophages co-cultured with losartan showed low production of IL-1beta (3907.50 +/- 143.61; P < 0.05) and low production of NALP3, caspase-1mRNA (29.82 +/- 6.92; 1.12 +/- 0.05, P < 0.05 for both). Losartan did not reduce IL-1beta mRNA(P > 0.05). Our results show that the NALP3 inflammasome is up-regulated and activated in the mouse macrophage in response to LPS + ATP stimulation. Losartan is able to suppress the LPS + ATP-induced production of IL-1beta protein. In addition, this effectmay be partially mediated by suppressing NALP3 inflammasome activation.

PMID:25272939 Wang F et al; Pharmazie 69 (9): 680-4 (2014)

The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar-kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid-inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II-SGK1-NHE3 of intra-renal tissue.

PMID:25119059 Fan X et al; Mol Med Rep 10 (5): 2483-8 (2014)

For more Mechanism of Action (Complete) data for Losartan (7 total), please visit the HSDB record page.

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