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

Similar Structures

Synonyms

Espirapril
Spirapril
Spiraprilum

External IDs

Sch 33844

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Spirapril hydrochloride	OCC25LM897	94841-17-5	CLDOLNORSLLQDI-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.

Target	Actions	Organism
AAngiotensin-converting enzyme	inhibitor	Humans

Absorption

Bioavailability is 50% following oral administration.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic. Converted to spiraprilat following oral administration.

Spirapril
Spiraprilat

Route of elimination

Not Available

Half life

30 to 35 hours

Clearance

Not Available

Toxicity

Not Available

Affected organisms

Humans and other mammals

Pathways

Pathway	Category
Spirapril Action Pathway	Drug action
Spirapril Metabolism Pathway	Drug metabolism

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid	Spirapril may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
1-benzylimidazole	1-benzylimidazole may decrease the antihypertensive activities of Spirapril.
2,5-Dimethoxy-4-ethylamphetamine	2,5-Dimethoxy-4-ethylamphetamine may decrease the antihypertensive activities of Spirapril.
2,5-Dimethoxy-4-ethylthioamphetamine	2,5-Dimethoxy-4-ethylthioamphetamine may decrease the antihypertensive activities of Spirapril.
4-Bromo-2,5-dimethoxyamphetamine	4-Bromo-2,5-dimethoxyamphetamine may decrease the antihypertensive activities of Spirapril.
4-Methoxyamphetamine	4-Methoxyamphetamine may decrease the antihypertensive activities of Spirapril.
5-methoxy-N,N-dimethyltryptamine	5-methoxy-N,N-dimethyltryptamine may decrease the antihypertensive activities of Spirapril.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Spirapril.
Abediterol	Abediterol may decrease the antihypertensive activities of Spirapril.
Acebutolol	The risk or severity of hyperkalemia can be increased when Acebutolol is combined with 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

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]
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]
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]
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
KEGG Drug: D08529
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

Property	Value	Source
Water Solubility	0.0293 mg/mL	ALOGPS
logP	1.79	ALOGPS
logP	1.6	ChemAxon
logS	-4.2	ALOGPS
pKa (Strongest Acidic)	3.62	ChemAxon
pKa (Strongest Basic)	5.2	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	95.94 Å²	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	121.94 m³·mol^-1	ChemAxon
Polarizability	48.74 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

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 inhibitor	Non-inhibitor	0.7259
CYP450 2D6 inhibitor	Non-inhibitor	0.8813
CYP450 2C19 inhibitor	Non-inhibitor	0.5956
CYP450 3A4 inhibitor	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not 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

Details1. Angiotensin-converting enzyme

Kind: Protein
Organism: Humans
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

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]
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]
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]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Transporters

Details1. Solute carrier family 15 member 1

Kind: Protein
Organism: Humans
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

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]

Details2. Solute carrier family 15 member 2

Kind: Protein
Organism: Humans
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

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 March 08, 2019 19:29

Spirapril

Identification

Structure for Spirapril (DB01348)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Transporters

References

References