Cilazapril
Basic information
- CAS
88768-40-5- Standard SMILES
CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCCN2CCC[C@@H](C(=O)O)N2C1=O- InChIKey
HHHKFGXWKKUNCY-FHWLQOOXSA-N- Molecular formula
- C22H31N3O5
- Average molar mass
- 417.5 g/mol
- Monoisotopic mass
- 417.2263711
Overview
Cilazapril is a pyridazinodiazepine resulting from the formal condensation of the carboxy group of cilazaprilat with ethanol. It is a drug used in the treatment of hypertension and heart failure. It has a role as an EC 3.4.15.1 (peptidyl-dipeptidase A) inhibitor, an antihypertensive agent and a prodrug. It is an ethyl ester, a dicarboxylic acid monoester and a pyridazinodiazepine. It is functionally related to a Cilazaprilat.
Names & identifiers
- Preferred name
- Cilazapril
- IUPAC
- (4S,7S)-7-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-6-oxo-1,2,3,4,7,8,9,10-octahydropyridazino[1,2-a]diazepine-4-carboxylic acid
- English name
- Cilazapril
- Molecular formula
- C22H31N3O5
- Molecular weight
- 417.5
Names & synonyms
cilazapril88768-40-5InhibaceCilazapril anhydrousCilazaprilumVascaceJustorAnhydrous cilazaprilRo 34-2848InitissDTXSID1048629Ro-312848006
Show more names
(1S,9S)-YipingshuRo34-2848Ro 31-2848Ro-34-2848CILASTATIN NACilazapril USP/EP/BP
CHEBI:36986H-Pyridazino(1,2-a)(1,2)diazepine-1-carboxylic acid, 9-(((1S)-1-(ethoxycarbonyl)-3-phenylpropyl)amino)octahydro-10-oxo-, (1S,9S)-8Q9454114QDTXCID8028555RO-31-2848/006(1S,9S)-9-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-10-oxo-octahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acidCilazapril, AnhydrousRo 31-2848/006
Database identifiers
- CAS
88768-40-5、92077-78-6- PubChem CID
- 56330
- DTXSID
DTXSID1048629- ChEMBL
CHEMBL515606- ChEBI
CHEBI:3698- UNII
- 8Q9454114Q
Properties
Computed structural properties
- XLogP
- 0.6
- Topological polar surface area
- 99.2 Ų
- Hydrogen bond donors
- 2
- Hydrogen bond acceptors
- 7
- Rotatable bonds
- 9
- Heavy atoms
- 30
- Formal charge
- 0
- Complexity
- 608
Experimental & physicochemical properties
Drugs
Pharmaceuticals -> Listed in ZINC15
Pharmaceuticals -> Antihypertensives
LogP0.55
Solubility
Water (25 ºC) 0.5 g/100 mL
1.06e+00 g/L
Human DrugsPharmaceuticals
Physical DescriptionSolid
Physicochemical properties
- Melting point
- 95 · 95-97°C
- Boiling point
- 598.1 · 598.1±60.0 °C(Predicted)
- Density
- 1.26 · 1.26±0.1 g/cm3(Predicted)
- storage temp.
- 2 · 2-8°C
- solubility
- Chloroform (Slightly), Ethanol (Slightly, Sonicated), Methanol (Slightly)
- form
- powder
- pka
- 2.28 · 2.28±0.20(Predicted)
Safety & regulation
Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.
Toxicology
Drug Induced Liver Injury
Drug-Induced Liver Injury Severity and Toxicity (DILIst)
CILAZAPRIL
DILI Positive
Oral
DOI:10.1016/j.drudis.2019.09.022
Safety data
- wgk
- 3
- rtecs
- MJ9650200
- Signal word
- Warning
- Symbol(GHS)
- GHS07
- safety_code
- 22-24/25
- Hazard statements
- H302-H315-H319-H335
- Precautionary statements
- P261-P280-P301+P312-P302+P352-P305+P351+P338
Chemistry & industry
Pharmacology
ATC Code
C09AA08
C - Cardiovascular system
QC - Cardiovascular system
Protein Binding
Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition.
Pharmacodynamics
Cilazapril inhibits the production angiotensin II. By doing so, it decreases sodium and water reabsorption (via aldosterone) and it decreases vasoconstriction. The combined effect of this is a decrease in vascular resistance, and therefore, blood pressure. The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition.
Mechanism of Action
Cilazapril is a pyridazine ACE inhibitor. It competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. As angiotensin II is a vasoconstrictor and a negative feedback mediator for renin activity, lower angiotensin II levels results in a decrease in blood pressure, an increase in renin activity, and stimulation of baroreceptor reflex mechanisms. Kininase II, an enzyme which degrades the vasodilator bradykinin, is identical to ACE and may also be inhibited.
Biological Half-LifeHalf-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively.
MeSH Pharmacological Classification
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