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Identification
NameSpirapril
Accession NumberDB01348
Typesmall molecule
Groupsapproved
Description

Spirapril is an ACE inhibitor antihypertensive drug used to treat hypertension. Like many ACE inhibitors, this is a prodrug which is converted to the active metabolite spiraprilat following oral administration. ACE inhibitors are used primarily in treatment of hypertension and congestive heart failure.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
RenormaxNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number83647-97-6
WeightAverage: 466.614
Monoisotopic: 466.15961346
Chemical FormulaC22H30N2O5S2
InChI KeyHRWCVUIFMSZDJS-SZMVWBNQSA-N
InChI
InChI=1S/C22H30N2O5S2/c1-3-29-21(28)17(10-9-16-7-5-4-6-8-16)23-15(2)19(25)24-14-22(30-11-12-31-22)13-18(24)20(26)27/h4-8,15,17-18,23H,3,9-14H2,1-2H3,(H,26,27)/t15-,17-,18-/m0/s1
IUPAC Name
(8S)-7-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(O)=O)SCCS2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsAlpha Amino Acid Esters; N-acyl-alpha Amino Acids; Alpha Amino Acid Amides; Phenylpropylamines; Pyrrolidine Carboxylic Acids; Dithioketals; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Dithiolanes; Carboxylic Acid Esters; Tertiary Amines; Ethers; Dialkylamines; Carboxylic Acids; Enolates; Polyamines; Thioethers
Substituentsn-acyl-alpha amino acid or derivative; alpha-amino acid ester; n-acyl-alpha-amino acid; alpha-amino acid amide; alpha-amino acid or derivative; phenylpropylamine; pyrrolidine carboxylic acid or derivative; pyrrolidine carboxylic acid; fatty acid ester; dithioketal; dicarboxylic acid derivative; benzene; tertiary carboxylic acid amide; thioacetal; pyrrolidine; dithiolane; tertiary amine; carboxamide group; carboxylic acid ester; polyamine; secondary amine; secondary aliphatic amine; carboxylic acid; thioether; enolate; ether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationSpirapril is an ACE inhibitor class drug used to treat hypertension.
PharmacodynamicsSpirapril is an angiotensin-converting enzyme (ACE) inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. By blocking ACE, spirapril decreases angiotensin II which is a vasoconstrictor and inducer of aldosterone. So by inhibiting the enzymes, aldosterone secreation is decreased (so less sodium is reabsorbed) and there is a decrease in vasoconstriction. Combined, this leades to a decrease in blood pressure.
Mechanism of actionSpiraprilat, the active metabolite of spirapril, 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. Spiraprilat may also act on kininase II, an enzyme identical to ACE that degrades the vasodilator bradykinin.
AbsorptionBioavailability is 50% following oral administration.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic. Converted to spiraprilat following oral administration.

SubstrateEnzymesProduct
Spirapril
Not Available
SpiraprilatDetails
Route of eliminationNot Available
Half life30 to 35 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Spirapril Action PathwayDrug actionSMP00156
Spirapril Metabolism PathwayDrug metabolismSMP00598
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.5287
Blood Brain Barrier - 0.9614
Caco-2 permeable - 0.83
P-glycoprotein substrate Substrate 0.8223
P-glycoprotein inhibitor I Non-inhibitor 0.6938
P-glycoprotein inhibitor II Non-inhibitor 0.7426
Renal organic cation transporter Non-inhibitor 0.8836
CYP450 2C9 substrate Non-substrate 0.833
CYP450 2D6 substrate Non-substrate 0.8553
CYP450 3A4 substrate Non-substrate 0.5658
CYP450 1A2 substrate Non-inhibitor 0.8439
CYP450 2C9 substrate Non-inhibitor 0.7259
CYP450 2D6 substrate Non-inhibitor 0.8813
CYP450 2C19 substrate Non-inhibitor 0.5956
CYP450 3A4 substrate Inhibitor 0.5073
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6331
Ames test Non AMES toxic 0.8764
Carcinogenicity Non-carcinogens 0.908
Biodegradation Not ready biodegradable 0.9115
Rat acute toxicity 2.2396 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9961
hERG inhibition (predictor II) Non-inhibitor 0.5579
Pharmacoeconomics
Manufacturers
  • Schering corp
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility2.93e-02 g/lALOGPS
logP1.79ALOGPS
logP1.6ChemAxon
logS-4.2ALOGPS
pKa (strongest acidic)3.62ChemAxon
pKa (strongest basic)5.2ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area95.94ChemAxon
rotatable bond count10ChemAxon
refractivity121.94ChemAxon
polarizability48.74ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Hannedouche T, Ikeni A, Marques LP, Natov S, Dechaux M, Schmitt F, Lacour B, Grunfeld JP: Renal effects of angiotensin II in normotensive subjects on short-term cilazapril treatment. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S25-7. Pubmed
  2. Noble S, Sorkin EM: Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs. 1995 May;49(5):750-66. Pubmed
  3. Rosendorff C, Patton J, Radford HM, Kalliatakis B: Alpha-adrenergic and angiotensin II pressor sensitivity in hypertensive patients treated with an angiotensin-converting enzyme inhibitor. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S105-9. Pubmed
  4. Shohat J, Wittenberg C, Erman A, Rosenfeld J, Boner G: Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension. Scand J Urol Nephrol. 1999 Feb;33(1):57-62. Pubmed
External Links
ResourceLink
PubChem Compound5311447
PubChem Substance46506126
ChemSpider4470933
BindingDB50017124
Therapeutic Targets DatabaseDAP000911
PharmGKBPA164776913
WikipediaSpirapril
ATC CodesC09AA11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AmilorideIncreased risk of hyperkalemia
LithiumThe ACE inhibitor increases serum levels of lithium
PotassiumIncreased risk of hyperkalemia
TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
TriamtereneIncreased risk of hyperkalemia
Food Interactions
  • Avoid alcohol.
  • Do not take calcium, aluminum, magnesium or iron supplements within 2 hours of taking this medication.
  • Herbs that may attenuate the antihypertensive effect of spirapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of spirapril.
  • Spirapril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.

Targets

1. Angiotensin-converting enzyme

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Angiotensin-converting enzyme P12821 Details

References:

  1. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207-24. Pubmed
  2. Maul B, Krause W, Pankow K, Becker M, Gembardt F, Alenina N, Walther T, Bader M, Siems WE: Central angiotensin II controls alcohol consumption via its AT1 receptor. FASEB J. 2005 Sep;19(11):1474-81. Pubmed
  3. Hermida RC, Ayala DE, Fontao MJ, Mojon A, Alonso I, Fernandez JR: Administration-time-dependent effects of spirapril on ambulatory blood pressure in uncomplicated essential hypertension. Chronobiol Int. 2010 May;27(3):560-74. Pubmed
  4. Arend U, Albrecht S, Meisel E, Schmidt J: [Influence of ACE inhibitor spirapril on left ventricular hypertrophy] Fortschr Med Orig. 2002 Dec 5;120(4):147-50. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Transporters

1. Solute carrier family 15 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 1 P46059 Details

References:

  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed

2. Solute carrier family 15 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 2 Q16348 Details

References:

  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed

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Drug created on June 30, 2007 12:15 / Updated on September 16, 2013 17:14