Identification

Name
Spirapril
Accession Number
DB01348
Type
Small Molecule
Groups
Approved
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
Product Ingredients
IngredientUNIICASInChI Key
Spirapril hydrochlorideOCC25LM89794841-17-5CLDOLNORSLLQDI-OOAIBONUSA-N
International/Other Brands
Renormax
Categories
UNII
96U2K78I3V
CAS number
83647-97-6
Weight
Average: 466.614
Monoisotopic: 466.15961346
Chemical Formula
C22H30N2O5S2
InChI Key
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)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(O)=O)SCCS2

Pharmacology

Indication

Spirapril is an ACE inhibitor class drug used to treat hypertension.

Pharmacodynamics

Spirapril 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 action

Spiraprilat, 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.

TargetActionsOrganism
AAngiotensin-converting enzyme
inhibitor
Human
Absorption

Bioavailability is 50% following oral administration.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic. Converted to spiraprilat following oral administration.

Route of elimination
Not Available
Half life

30 to 35 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Spirapril Action PathwayDrug action
Spirapril Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidSpirapril may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Spirapril.
AceclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Aceclofenac is combined with Spirapril.
AcemetacinThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acemetacin is combined with Spirapril.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Spirapril.
AgmatineThe risk or severity of hyperkalemia can be increased when Spirapril is combined with Agmatine.
Agrostis gigantea pollenThe risk or severity of adverse effects can be increased when Spirapril is combined with Agrostis gigantea pollen.
Agrostis stolonifera pollenThe risk or severity of adverse effects can be increased when Spirapril is combined with Agrostis stolonifera pollen.
AlclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Alclofenac is combined with Spirapril.
AlfuzosinAlfuzosin may increase the hypotensive activities of Spirapril.
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.

References

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
Human Metabolome Database
HMDB0015438
PubChem Compound
5311447
PubChem Substance
46506126
ChemSpider
4470933
BindingDB
50017124
ChEBI
135756
ChEMBL
CHEMBL431
Therapeutic Targets Database
DAP000911
PharmGKB
PA164776913
Wikipedia
Spirapril
ATC Codes
C09AA11 — Spirapril

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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 RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
N-acyl-L-alpha-amino acids / Alpha amino acid esters / Alpha amino acid amides / Pyrrolidine carboxylic acids / N-acylpyrrolidines / Fatty acid esters / Dithioketals / Aralkylamines / Dicarboxylic acids and derivatives / Benzene and substituted derivatives
show 12 more
Substituents
Alpha-dipeptide / Alpha-amino acid ester / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Alpha-amino acid amide / Alpha-amino acid or derivatives / N-acylpyrrolidine / Pyrrolidine carboxylic acid / Pyrrolidine carboxylic acid or derivatives
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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...
Gene Name
ACE
Uniprot ID
P12821
Uniprot Name
Angiotensin-converting enzyme
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
Uniprot Name
Solute carrier family 15 member 1
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
Uniprot Name
Solute carrier family 15 member 2
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]

Drug created on June 30, 2007 12:15 / Updated on November 02, 2018 08:51