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87679-37-6 molecular structure
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(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid

ChemBase ID: 401
Molecular Formular: C24H34N2O5
Molecular Mass: 430.53716
Monoisotopic Mass: 430.2467722
SMILES and InChIs

SMILES:
O=C(N1[C@@H]2[C@@H](C[C@H]1C(=O)O)CCCC2)[C@@H](N[C@@H](CCc1ccccc1)C(=O)OCC)C
Canonical SMILES:
CCOC(=O)[C@@H](N[C@H](C(=O)N1[C@H]2CCCC[C@@H]2C[C@H]1C(=O)O)C)CCc1ccccc1
InChI:
InChI=1S/C24H34N2O5/c1-3-31-24(30)19(14-13-17-9-5-4-6-10-17)25-16(2)22(27)26-20-12-8-7-11-18(20)15-21(26)23(28)29/h4-6,9-10,16,18-21,25H,3,7-8,11-15H2,1-2H3,(H,28,29)/t16-,18+,19-,20-,21-/m0/s1
InChIKey:
VXFJYXUZANRPDJ-WTNASJBWSA-N

Cite this record

CBID:401 http://www.chembase.cn/molecule-401.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
IUPAC Traditional name
trandolapril
Brand Name
Mavik
Synonyms
Odrik
Gopten
RU-44570
Trandolaprilum [Latin]
Trandolapril
(2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-Indole-2-carboxylic acid
Mavik
Trandolapril
CAS Number
87679-37-6
MDL Number
MFCD00865776
PubChem SID
46508300
160963864
PubChem CID
5484727

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem ALOGPS 2.1
Acid pKa 3.799918  H Acceptors
H Donor LogD (pH = 5.5) 1.702222 
LogD (pH = 7.4) 0.2851026  Log P 1.9473588 
Molar Refractivity 115.7878 cm3 Polarizability 46.047737 Å3
Polar Surface Area 95.94 Å2 Rotatable Bonds 10 
Lipinski's Rule of Five true 
Log P 1.31  LOG S -4.32 
Solubility (Water) 2.07e-02 g/l 

PROPERTIES

PROPERTIES

Physical Property Safety Information Product Information Bioassay(PubChem)
Solubility
Chloroform expand Show data source
DMSO expand Show data source
DMSO: ≥20 mg/mL expand Show data source
Methanol expand Show data source
Apperance
white powder expand Show data source
White Solid expand Show data source
Melting Point
122-123°C expand Show data source
Hydrophobicity(logP)
3.5 expand Show data source
Storage Condition
-20°C Freezer expand Show data source
RTECS
NL6015178 expand Show data source
MSDS Link
Download expand Show data source
Download expand Show data source
German water hazard class
3 expand Show data source
Personal Protective Equipment
Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter expand Show data source
Storage Temperature
room temp expand Show data source
Purity
≥98% (HPLC) expand Show data source
Certificate of Analysis
Download expand Show data source
Empirical Formula (Hill Notation)
C24H34N2O5 expand Show data source

DETAILS

DETAILS

DrugBank DrugBank Sigma Aldrich Sigma Aldrich TRC TRC
DrugBank - DB00519 external link
Item Information
Drug Groups approved
Description Trandolapril is a non-sulhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to its biologically active diacid form, trandolaprilat, in the liver. Trandolaprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Trandolapril may be used to treat mild to moderate hypertension, to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, as an adjunct treatment for congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
Indication For the treatment of mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure (CHF), to improve survival following myocardial infarction (MI) in individuals who are hemodynamically stable and demonstrate symptoms of left ventricular systolic dysfunction or signs of CHF within a few days following acute MI, and to slow progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.
Pharmacology Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure via a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention.
Toxicity Most likely clinical manifestations of overdose are symptoms of severe hypotension. Most common adverse effects include cough, headache and dizziness. The oral LD50 of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.
Affected Organisms
Humans and other mammals
Biotransformation Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion to trandolaprilat, the active metabolite. Seven other metabolites, including diketopiperazine and glucuronide conjugated derivatives of trandolapril and trandolaprilat, have been identified.
Absorption ~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14%
Half Life The elimination half lives of trandolapril and trandolaprilat are about 6 and 10 hours, respectively, but, similar to all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase that involves a small fraction of administered drug. This likely represents drug binding to plasma and tissue ACE. The effective half life of elimination for trandolaprilat is 16-24 hours.
Protein Binding Serum protein binding of trandolapril is ~ 80% (independent of concentration and not saturable) while that of trandolaprilat is 65 to 94% (concentration-dependent and saturable).
Elimination After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces.
Distribution * 18 L
Clearance * 52 L/h [After approximately 2 mg IV doses]
References
Berl T: Review: renal protection by inhibition of the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):1-8. [Pubmed]
Conen H, Brunner HR: Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J. 1993 May;125(5 Pt 2):1525-31. [Pubmed]
Diaz A, Ducharme A: Update on the use of trandolapril in the management of cardiovascular disorders. Vasc Health Risk Manag. 2008;4(6):1147-58. [Pubmed]
Guay DR: Trandolapril: a newer angiotensin-converting enzyme inhibitor. Clin Ther. 2003 Mar;25(3):713-75. [Pubmed]
Jouquey S, Stepniewski JP, Hamon G: Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S16-8. [Pubmed]
Reynolds NA, Wagstaff AJ, Keam SJ: Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension. Drugs. 2005;65(13):1893-914. [Pubmed]
Rubio-Guerra AF, Vargas-Robles H, Vargas-Ayala G, Rodriguez-Lopez L, Escalante-Acosta BA: The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin Exp Hypertens. 2008 Oct;30(7):682-8. [Pubmed]
Sanbe A, Tanonaka K, Kobayasi R, Takeo S: Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol. 1995 Oct;27(10):2209-22. [Pubmed]
Torp-Pedersen C, Kober L: Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet. 1999 Jul 3;354(9172):9-12. [Pubmed]
Trandolapril: an ACE inhibitor for treatment of hypertension. Med Lett Drugs Ther. 1996 Nov 22;38(988):104-5. [Pubmed]
Wiseman LR, McTavish D: Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994 Jul;48(1):71-90. [Pubmed]
Zannad F: Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46 Suppl 2:172-81; discussion 182. [Pubmed]
External Links
Wikipedia
RxList
PDRhealth
Drugs.com
Sigma Aldrich - T4827 external link
Biochem/physiol Actions
Trandolapril is an ACE inhibitor. Trandolapril differs from other ACE inhibitors in that it has a longer biological half-life and a high degree of lipophilicity.
Other Notes
Tandem Mass Spectrometry data independently generated by Scripps Center for Metabolomics is available to view or download in PDF. T4827.pdf Tested metabolites are featured on Scripps Center for Metabolomics METLIN Metabolite Database. To learn more, visit sigma.com/metlin.
Toronto Research Chemicals - T713500 external link
An antihypertensive. Angiotensin converting enzyme (ACE) inhibitor.

REFERENCES

REFERENCES

From Suppliers Google Scholar IconGoogle Scholar PubMed iconPubMed Google Books IconGoogle Books
  • • Berl T: Review: renal protection by inhibition of the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):1-8. Pubmed
  • • Conen H, Brunner HR: Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J. 1993 May;125(5 Pt 2):1525-31. Pubmed
  • • Diaz A, Ducharme A: Update on the use of trandolapril in the management of cardiovascular disorders. Vasc Health Risk Manag. 2008;4(6):1147-58. Pubmed
  • • Guay DR: Trandolapril: a newer angiotensin-converting enzyme inhibitor. Clin Ther. 2003 Mar;25(3):713-75. Pubmed
  • • Jouquey S, Stepniewski JP, Hamon G: Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S16-8. Pubmed
  • • Reynolds NA, Wagstaff AJ, Keam SJ: Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension. Drugs. 2005;65(13):1893-914. Pubmed
  • • Rubio-Guerra AF, Vargas-Robles H, Vargas-Ayala G, Rodriguez-Lopez L, Escalante-Acosta BA: The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin Exp Hypertens. 2008 Oct;30(7):682-8. Pubmed
  • • Sanbe A, Tanonaka K, Kobayasi R, Takeo S: Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol. 1995 Oct;27(10):2209-22. Pubmed
  • • Torp-Pedersen C, Kober L: Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet. 1999 Jul 3;354(9172):9-12. Pubmed
  • • Trandolapril: an ACE inhibitor for treatment of hypertension. Med Lett Drugs Ther. 1996 Nov 22;38(988):104-5. Pubmed
  • • Wiseman LR, McTavish D: Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994 Jul;48(1):71-90. Pubmed
  • • Zannad F: Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46 Suppl 2:172-81; discussion 182. Pubmed
  • • Brown, N.L., et al.: Eur. J. Pharmacol., 148, 79 (1988)
  • • Kober, L., et al.: N. Engl. J. Med., 333, 1670 (1988)
  • • Malik, R.A., et al.: Lancet, 352, 1978 (1998)
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