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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
Synonyms
Renormax
Spirapril
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
RenormaxNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Spirapril hydrochloride
ThumbNot applicableDBSALT001443
Categories
UNII96U2K78I3V
CAS number83647-97-6
WeightAverage: 466.614
Monoisotopic: 466.15961346
Chemical FormulaC22H30N2O5S2
InChI KeyInChIKey=HRWCVUIFMSZDJS-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)[[email protected]](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CC2(C[[email protected]]1C(O)=O)SCCS2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 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.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentPeptides
Alternative Parents
Substituents
  • Alpha peptide
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Alpha-amino acid ester
  • Alpha-amino acid amide
  • Phenylpropylamine
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Pyrrolidine carboxylic acid or derivatives
  • Pyrrolidine carboxylic acid
  • N-acylpyrrolidine
  • Aralkylamine
  • Fatty acid ester
  • Dithioketal
  • Fatty acyl
  • Benzenoid
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • 1,3-dithiolane
  • Tertiary carboxylic acid amide
  • Pyrrolidine
  • Dithiolane
  • Thioacetal
  • Tertiary amine
  • Carboxylic acid ester
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Dialkylthioether
  • Thioether
  • Secondary amine
  • Secondary aliphatic amine
  • Carboxylic acid
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption-0.5287
Blood Brain Barrier-0.9614
Caco-2 permeable-0.83
P-glycoprotein substrateSubstrate0.8223
P-glycoprotein inhibitor INon-inhibitor0.6938
P-glycoprotein inhibitor IINon-inhibitor0.7426
Renal organic cation transporterNon-inhibitor0.8836
CYP450 2C9 substrateNon-substrate0.833
CYP450 2D6 substrateNon-substrate0.8553
CYP450 3A4 substrateNon-substrate0.5658
CYP450 1A2 substrateNon-inhibitor0.8439
CYP450 2C9 inhibitorNon-inhibitor0.7259
CYP450 2D6 inhibitorNon-inhibitor0.8813
CYP450 2C19 inhibitorNon-inhibitor0.5956
CYP450 3A4 inhibitorInhibitor0.5073
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6331
Ames testNon AMES toxic0.8764
CarcinogenicityNon-carcinogens0.908
BiodegradationNot ready biodegradable0.9115
Rat acute toxicity2.2396 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9961
hERG inhibition (predictor II)Non-inhibitor0.5579
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0293 mg/mLALOGPS
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 Area95.94 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity121.94 m3·mol-1ChemAxon
Polarizability48.74 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  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:1382161 ]
  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:7601014 ]
  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:1382157 ]
  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:10100366 ]
External Links
ATC CodesC09AA11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.
Gene Name:
ACE
Uniprot ID:
P12821
Molecular Weight:
149713.675 Da
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:11929321 ]
  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:16126915 ]
  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. doi: 10.3109/07420528.2010.485411. [PubMed:20524801 ]
  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:12613273 ]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function:
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name:
SLC15A1
Uniprot ID:
P46059
Molecular Weight:
78805.265 Da
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. doi: 10.1124/jpet.108.143339. Epub 2008 Aug 19. [PubMed:18713951 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Peptide:proton symporter activity
Specific Function:
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
Gene Name:
SLC15A2
Uniprot ID:
Q16348
Molecular Weight:
81782.77 Da
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. doi: 10.1124/jpet.108.143339. Epub 2008 Aug 19. [PubMed:18713951 ]
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Drug created on June 30, 2007 12:15 / Updated on August 17, 2016 12:23