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Benazeprilat
Also known as: 86541-75-5, Benazeprilum [latin], Benazeprilum, Lotrel, Benazepril sandoz, Cgs-14824a
Molecular Formula
C24H28N2O5
Molecular Weight
424.5  g/mol
InChI Key
XPCFTKFZXHTYIP-PMACEKPBSA-N
FDA UNII
UDM7Q7QWP8

Benazepril is a carboxyl-containing angiotensin-converting enzyme (ACE) inhibitor with antihypertensive activity. As a prodrug, benazepril is metabolized to its active form benazeprilat. Benazeprilat competitively binds to and inhibits ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This prevents the potent vasoconstrictive actions of angiotensin II resulting in vasodilation. Benazeprilat also decreases angiotensin II-induced aldosterone secretion by the adrenal cortex, which leads to an increase in sodium excretion and subsequently increases water outflow.
Benazepril is an Angiotensin Converting Enzyme Inhibitor. The mechanism of action of benazepril is as an Angiotensin-converting Enzyme Inhibitor. The physiologic effect of benazepril is by means of Decreased Blood Pressure.
1 2D Structure

Benazeprilat

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid
2.1.2 InChI
InChI=1S/C24H28N2O5/c1-2-31-24(30)20(14-12-17-8-4-3-5-9-17)25-19-15-13-18-10-6-7-11-21(18)26(23(19)29)16-22(27)28/h3-11,19-20,25H,2,12-16H2,1H3,(H,27,28)/t19-,20-/m0/s1
2.1.3 InChI Key
XPCFTKFZXHTYIP-PMACEKPBSA-N
2.1.4 Canonical SMILES
CCOC(=O)C(CCC1=CC=CC=C1)NC2CCC3=CC=CC=C3N(C2=O)CC(=O)O
2.1.5 Isomeric SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@H]2CCC3=CC=CC=C3N(C2=O)CC(=O)O
2.2 Other Identifiers
2.2.1 UNII
UDM7Q7QWP8
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Benazapril

2. Benazepril Hydrochloride

3. Benzazepril

4. Briem

5. Cgs-14824-a

6. Cgs-14824a

7. Cibacne

8. Cibacen

9. Labopal

10. Lotensin

2.3.2 Depositor-Supplied Synonyms

1. 86541-75-5

2. Benazeprilum [latin]

3. Benazeprilum

4. Lotrel

5. Benazepril Sandoz

6. Cgs-14824a

7. Forteekor

8. Cibacen Ws

9. Benazepril (inn)

10. 2-[(3s)-3-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3h-1-benzazepin-1-yl]acetic Acid

11. C09aa07

12. Udm7q7qwp8

13. Chembl838

14. Chebi:3011

15. 1h-1-benzazepine-1-acetic Acid, 3-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-, (s-(r*,r*))-

16. [(3s)-3-{[(1s)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}-2-oxo-2,3,4,5-tetrahydro-1h-1-benzazepin-1-yl]acetic Acid

17. 109010-10-8

18. Benazepril [inn]

19. Benazepril [inn:ban]

20. Cgs-14824-a

21. Benazepril Free Base

22. [(3s)-3-{[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-2-oxo-2,3,4,5-tetrahydro-1h-1-benzazepin-1-yl]acetic Acid

23. 2-((s)-3-(((s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-2-oxo-2,3,4,5-tetrahydro-1h-benzo[b]azepin-1-yl)acetic Acid

24. 2-[(3s)-3-{[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-2-oxo-2,3,4,5-tetrahydro-1h-1-benzazepin-1-yl]acetic Acid

25. Benazepril Sandoz (tn)

26. Unii-udm7q7qwp8

27. Forteekor [veterinary] (tn)

28. ((3s)-3-(((1s)-1-(ethoxycarbonyl)-3-phenylpropyl)amino)-2-oxo-2,3,4,5-tetrahydro-1h-1-benzazepin-1-yl)acetic Acid

29. 1h-1-benzazepine-1-acetic Acid, 3-(((1s)-1-(ethoxycarbonyl)-3-phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-, (3s)-

30. 1h-1-benzazepine-1-acetic Acid, 3-[[(1s)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3s)-

31. Benazepril Impurity A

32. Spectrum_001922

33. Benazepril [mi]

34. Spectrum2_000482

35. Spectrum3_001674

36. Spectrum4_000286

37. Spectrum5_001546

38. Benazepril [vandf]

39. Benazepril [who-dd]

40. Schembl16396

41. Bspbio_003487

42. Kbiogr_000812

43. Kbioss_002464

44. Mls006011854

45. Bidd:gt0800

46. Spbio_000343

47. Gtpl6374

48. Dtxsid5022645

49. Hsdb 7081

50. Kbio2_002457

51. Kbio2_005025

52. Kbio2_007593

53. Kbio3_002707

54. Bcp12672

55. Hy-b0093

56. Zinc3781943

57. Bbl034011

58. Bdbm50021153

59. Mfcd00864466

60. S5938

61. Stk627447

62. Akos005560204

63. Cs-1795

64. Db00542

65. Benazepril [ema Epar Veterinary]

66. Ncgc00165740-01

67. Ncgc00165740-02

68. Ncgc00165740-03

69. Ncgc00165740-04

70. [(3s)-3-({(1s)-1-[(ethyloxy)carbonyl]-3-phenylpropyl}amino)-2-oxo-2,3,4,5-tetrahydro-1h-1-benzazepin-1-yl]acetic Acid

71. Smr000857173

72. Sbi-0206744.p001

73. C06843

74. D07499

75. Ab00698518-07

76. Ab00698518_08

77. Ab00698518_09

78. 541b744

79. A841713

80. Q592802

81. Brd-k49807096-003-02-3

82. Tert Butyl-3-(3s) Amino-2,3,4,5-tetrahydro-1h(1) Benzazepin-2-one-1-acetate

83. Tert Butyl-3-(3s)amino-2,3,4,5-tetrahydro-1h(1)benzazepin-2-one-1-acetate

84. 2-((s)-3-((s)-1-ethoxy-1-oxo-4-phenylbutan-2-ylamino)-2-oxo-2,3,4,5-tetrahydro-1h-benzo[b]azepin-1-yl)acetic Acid

85. 2-[(3s)-3-[[(1s)-1-ethoxycarbonyl-3-phenyl-propyl]amino]-2-oxo-4,5-dihydro-3h-1-benzazepin-1-yl]acetic Acid;benazepril

86. 2-[(4s)-4-[[(1s)-1-ethoxycarbonyl-3-phenyl-propyl]amino]-3-oxo-2-azabicyclo[5.4.0]undeca-7,9,11-trien-2-yl]acetic Acid

2.3.3 Other Synonyms

1. 86541-78-8

2. Benazeprilate

3. Benazeprilat

2.4 Create Date
2005-06-24
3 Chemical and Physical Properties
Molecular Weight 424.5 g/mol
Molecular Formula C24H28N2O5
XLogP31.3
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count6
Rotatable Bond Count10
Exact Mass424.19982200 g/mol
Monoisotopic Mass424.19982200 g/mol
Topological Polar Surface Area95.9 Ų
Heavy Atom Count31
Formal Charge0
Complexity619
Isotope Atom Count0
Defined Atom Stereocenter Count2
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Benazepril is included in the database.

NIH/NLM; ClinicalTrials.Gov. Available from, as of August 30, 2017: https://clinicaltrials.gov/


Lotensin is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ... It may be used alone or in combination with thiazide diuretics. /Included in US product label/

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


ACE inhibitors have been used in the management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and beta-blockers. /Angiotensin-converting enzyme (ACE) inhibitors; NOT included in US product label/

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2067


Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. /Angiotensin-converting enzyme (ACE) inhibitors; NOT included in US product label/

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2067


For more Therapeutic Uses (Complete) data for Benazepril (7 total), please visit the HSDB record page.


4.2 Drug Warning

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

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


Rare angiotensin-converting enzyme (ACE) inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice; may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including benazepril, who develop jaundice or marked elevations of hepatic enzymes should discontinue the drug and receive appropriate monitoring.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2068


Serum potassium should be monitored periodically in patients receiving Lotensin. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


Adverse effects reported in greater than 1% of patients receiving benazepril include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with hydrochlorothiazide include dizziness, fatigue, postural dizziness, headache, cough, hypertonia, vertigo, nausea, impotence, and somnolence. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with amlodipine include cough, headache, dizziness, and edema.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2069


For more Drug Warnings (Complete) data for Benazepril (16 total), please visit the HSDB record page.


4.3 Drug Indication

Benazepril is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which, when hydrolyzed by esterases to its active Benazeprilat, is used to treat hypertension and heart failure, to reduce proteinuria and renal disease in patients with nephropathies, and to prevent stroke, myocardial infarction, and cardiac death in high-risk patients. Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.


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.)


Angiotensin-Converting Enzyme Inhibitors

A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. (See all compounds classified as Angiotensin-Converting Enzyme Inhibitors.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
BENAZEPRIL
5.3.2 FDA UNII
UDM7Q7QWP8
5.3.3 Pharmacological Classes
Angiotensin-converting Enzyme Inhibitors [MoA]; Decreased Blood Pressure [PE]; Angiotensin Converting Enzyme Inhibitor [EPC]
5.4 ATC Code

C09AA07

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

C09A - Ace inhibitors, plain

C09AA - Ace inhibitors, plain

C09AA07 - Benazepril


5.5 Absorption, Distribution and Excretion

Absorption

Bioavailability of oral dosing is 3% to 4% in horses. In humans at least 37% of oral benazepril is absorbed and reaches peak plasma concentration in 0.5 hours to 1 hour. Other studies have shown a peak plasma concentration at a median of 1.5 hours.


Route of Elimination

Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects.


Volume of Distribution

The final population pharmacokinetic model in one study estimated the volume of distribution to be 20369.9L.


Clearance

The final population pharmacokinetic model of one study estimates the clearance to be 12930.0L.


/MILK/ Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an orally administered dose was recovered in urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal (i.e., biliary) excretion accounts for approximately 11% - 12% of benazeprilat excretion. The effective half-life of benazeprilat following once daily repeat oral administration of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily administration.

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


5.6 Metabolism/Metabolites

Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat are conjugated to glucuronic acid prior to urinary excretion.


Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an orally administered dose was recovered in urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal (i.e., biliary) excretion accounts for approximately 11% - 12% of benazeprilat excretion. The effective half-life of benazeprilat following once daily repeat oral administration of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily administration.

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


After oral dosing in healthy dogs, benazepril is rapidly absorbed and converted into the active metabolite benazeprilat with peak levels of benazeprilat occurring approximately 75 minutes after dosing.

Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 146


Benazepril is almost completely metabolized to benazeprilat by cleavage of the ester group (primarily in liver). Both benazepril and benazeprilat undergo glucuronidation.

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


5.7 Biological Half-Life

The half life of the prodrug benazepril is 2.78.5h. The half life of the active metabolite benazeprilat is 22.39.2h The accumulation half life of benazepril is 10 to 11 hours.


The elimination half life of benazeprilat is approximately 3.5 hours in healthy dogs. /Benazeprilat/

Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 146


The effective half-life of benazeprilat following once daily repeat oral administration of benazepril hydrochloride is 10 to 11 hours. /Benazeprilat/

NIH; DailyMed. Current Medication Information for Lotensin (Benazepril Hydrochloride Tablet) (Updated: August 2017). Available from, as of November 2, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2abb091b-a53e-46b0-9b84-e5ee8f2bdd8e


5.8 Mechanism of Action

Benazeprilat, the active metabolite of Benazepril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion.


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