Quinapril hydrochloride is a hydrochloride resulting from the reaction of equimolar amounts of quinapril and hydrogen chloride. A prodrug for quinaprilat hydrochloride (by hydrolysis of the ethyl ester to the corresponding carboxylic acid), it is used as an angiotensin-converting enzyme inhibitor (ACE inhibitor) for the treatment of hypertension and congestive heart failure. It has a role as an EC 3.4.15.1 (peptidyl-dipeptidase A) inhibitor and an antihypertensive agent. It contains a quinapril(1+).
CI 906NSC-75822233067B3N2MCHEBI:8714DTXCID501221AccuprillQuinilRefChem:57155
Database identifiers
CAS
82586-55-8
PubChem CID
54891
DTXSID
DTXSID3021221
ChEMBL
CHEMBL1201011
ChEBI
CHEBI:8714
UNII
33067B3N2M
EC Number
620-479-5
Properties
Computed structural properties
Topological polar surface area
95.9 Ų
Hydrogen bond donors
3
Hydrogen bond acceptors
6
Rotatable bonds
10
Heavy atoms
33
Formal charge
0
Complexity
648
Experimental & physicochemical properties
Solubility>71.2 [ug/mL] (The mean of the results at pH 7.4)
Human Drugs · 2 items
FDA approved drugs -> Active ingredient
FDA approved drugs -> Active ingredient
Melting Point120-130 °C (crystals from ethyl acetatetoluene) and 119-121.5 °C (crystals from acetonitrile)
Collision Cross Section203.5 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
Other Experimental Properties · 2 items
Crystals from ethyl acetate-toluene ... /with/ specific optical rotation at 23 °C for D (sodium) line = +14.5 deg (c = 1.2 in ethanol). Also reported as white crystalline solid from acetonitrile ... /with/ specific optical rotation at 25 °C for D (sodium) line = +15.4 deg (c = 2 in methanol).
White to off-white amorphous powder that is freely soluble in aqueous solvents
Physicochemical properties
Melting point
120 · 120-130°C
alpha
23 · D23 +14.5° (c = 1.2 in ethanol) (Klutchko); D25 +15.4° (c = 2 in methanol) (Goel, Krolls)
Safety & regulation
Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.
GHS classification
GHS Classification · 4 items
Warning
H361 (53%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]
P203, P280, P318, P405, and P501 (click each P-code to see the statement)
Aggregated GHS information provided per 66 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Hazard information
FDA Requirements · 1 item
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl quinapril hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
Hazard Classes and CategoriesRepr. 2 (53%)
Safety & protection
Storage ConditionsStorage: Store at controlled room temp 15-30 °C (59-86 °F). Protect from light.
Disposal Methods · 1 item
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
Toxicology
Interactions · 5 items
Chemistry & industry
Pharmacology
Mechanism of Action · 2 items
Block formation of angiotensin II, promoting vasodilation & decreased aldosterone; also increased bradykinin & vasodilatory prostaglandins. /ACE Inhibitors; from table/ /Salt not specified/
Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by iv administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small incr in serum potassium. In controlled hypertension trials, treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L ... . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). /Salt not specified/
Biological Half-LifeThe initial half-life of /the metabolite/ quinaprilat is about 2 hr; a prolonged terminal half-life of about 25 hr may be due to high-affinity binding of the drug to tissue ACE. /Salt not specified/
Metabolism/Metabolites · 2 items
Cleavage of the ester moiety by hepatic esterases transforms quinapril hydrochloride, a prodrug, into quinaprilat, an ACE inhibitor that in vitro is about as potent as benazeprilat. ... Quinapril is metabolized to quinaprilat & to other minor metabolites ... .
Hepatic.
Route of Elimination: Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose
Half Life: Elimination half life is 2 hours with a prolonged terminal phase of 25 hours.
6.1 C · 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects
Hazard Classifications
2 STOT · Repr. 2STOT RE 1
Hazardous Substances Data
82586 · 82586-55-8(Hazardous Substances Data)
Toxicity
50 in · Freely sol in aq solvents. LD50 in male, female mice, rats (mg/kg): 1739, 1840, 4280, 3541 orally; 504, 523, 158, 107 i.v. (Kaplan, 1989)
Hyperkalemia may occur with potassium supplements, potassium-sparing agents, & NSAIDs. /ACE inhibitors; from table/ /Salt not specified/
... ACE inhibitors enhance the efficacy of diuretic drugs. This means that even very small doses of diuretics may substantially improve the antihypertensive efficacy of ACE inhibitors; & on the other end of the spectrum, the use of high doses of diuretics together with angiotensin converting enzyme inhibitors may lead to excessive reduction in blood pressure & to /sodium ion/ loss in some patients. /ACE inhibitors/ /Salt not specified/
Oligopeptidic drugs such as beta-lactams & angiotensin-converting enzyme inhibitors share the same carriers in humans & animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concns were measured by liquid chromatography, & the data were analyzed by a noncompartmental method & by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. 5 groups of 8 rats were examined. In the first 3 groups, cephalexin elimination kinetics after intra-arterial admin alone or in combination with quinapril given by the parenteral or the oral route were studied, & the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral admin might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concns of cephalexin than those of quinapril. In the last 2 groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concn-time curve (AUC) for cephalexin was increased by ca. 30% by coadmin of quinapril (40.1 versus 31.4 mg.hr/liter; P=0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/hr/kg of body weight (P<0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 hr-1; P<0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level. /Salt not specified/
Concurrent use /of other hypotension-producing medications/ with ACE inhibitors may produce additive hypotensive effects. /ACE inhibitors/ /Salt not specified/
For more Interactions (Complete) data for QUINAPRIL HYDROCHLORIDE (16 total), please visit the HSDB record page.
Exposure Routes · 1 item
Peak plasma concentrations of quinapril occur within one hour following oral administration. The extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal.
Toxicity Summary · 1 item
There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Quinaprilat, the principle active metabolite of quinapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Quinaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Signs and SymptomsOverdose may lead to severe hypotension. The most common adverse effects observed in controlled clinical trials were dizziness, cough, chest pain, dyspnea, fatigue, and nausea/vomiting.
Human Toxicity Excerpts · 3 items
/HUMAN EXPOSURE STUDIES/ ACE inhibitors should be avoided in 2nd and 3rd trimesters because of severe fetal and neonatal toxicity (oligohydramnios, pulmonary hypoplasia, renal failure, anuria, death); severe, persistent, neonatal hypotension may occur. Structural defects after exposure in 2nd or 3rd trimesters include fetal calvarial hypoplasia and, possibly, renal anomalies. /ACE inhibitors; from table/ /Salt not specified/
/HUMAN EXPOSURE STUDIES/ Angioedema is an infrequent but serious and potentially fatal adverse effect of all the ACE inhibitors. Thus, patients starting treatment with these drugs should be explicitly warned to discontinue their use with the advent of any signs of angioedema. /ACE inhibitors/ /Salt not specified/
/SIGNS AND SYMPTOMS/ The principal adverse effect of ACE inhibitor overdose is hypotension, although hyperkalemia & renal failure may occur. ... /ACE inhibitors/ /Salt not specified/
Carcinogen ClassificationNo indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver Injury · 6 items
Drug Induced Liver Injury Rank (DILIrank 2.0)
Quinapril hydrochloride
vLess-DILI-concern
3
Adverse reactions
DOI:10.1016/j.drudis.2016.02.015
Non-Human Toxicity Excerpts · 4 items
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50-60 times the max human daily dose, respectively, on an mg/sq m basis and 3.8-10 times the max human daily dose when based on an mg/sq m basis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/sc lipomas.
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No teratogenic effects of ACCUPRIL were seen in studies of pregnant rats and rabbits. On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. /Salt not specified/
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the max daily human dose when based on mg/kg and mg/sq m, respectively). /Salt not specified/
/GENOTOXICITY/ Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured cells, and in an in vivo cytogenetic study with rat bone marrow. /Salt not specified/
Antidote and Emergency Treatment... Following gut decontamination, treatment is primarily supportive to maintain an adequate blood pressure. /ACE Inhibitors/ /Salt not specified/
Toxicity DataLD<sub>50</sub>=1739mg/kg (orally in mice)
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl quinapril hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
Safety data
PPE
Eyeshields, Gloves, type N95 (US)
wgk
2
rtecs
NW7176000
hs_code
2933492250
Toxicity
Freely sol in aq solvents. LD50 in male, female mice, rats (mg/kg): 1739, 1840, 4280, 3541 orally; 504, 523, 158, 107 i.v. (Kaplan, 1989)
Signal word
Warning
Symbol(GHS)
GHS08
safety_code
22-24/25
Storage Class
6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects
A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility.
Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.
Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume.
Absorption, Distribution and Excretion · 2 items
Absorption (bioavailability) of quinapril is 60%; time to peak serum concn is 2 hr; half-life (elimination) is 2 hr; protein binding is 97%; metabolism is in the liver. /from table/ /Salt not specified/
Quinapril is rapidly absorbed (peak concns are achieved in 1 hr, but the peak may be delayed after food), & its rate but not extent of oral absorption (60%) may be reduced by food. Quinapril is metabolized to quinaprilat & to other minor metabolites, & quinaprilat is excreted in the urine (61%) & the feces (37%). Peak concns of quinaprilat in plasma are achieved in about 2 hr. Conversion of quinapril to quinaprilat is reduced in patients with diminished liver function. The initial half-life of quinaprilat is about 2 hr; a prolonged terminal half-life of about 25 hr may be due to high-affinity binding of the drug to tissue ACE. /Salt not specified/
Uses & manufacturing
Uses · 2 items
Medication
For the treatment of hypertension and as adjunct therapy in the treatment of congestive heart failure. May also be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
Methods of ManufacturingPreparation: M.L. Hoefle, S. Klutchko, EP 49605; eidem, US 4344949 (both 1982 to Warner-Lambert)...Synthesis of novel crystalline and purified form: O.P. Goel, U. Krolls, US 4761479 (1988 to Warner-Lambert)
Acequide; Koretic /Mixture with Hydrochlorothiazide/
The main ingredient in the drug Accupril ... (tablets)
General Manufacturing Information · 2 items
The main ingredient in the drug Accuretic ... (tablets) /Mixture with Hydrochlorothiazide/
The major objective of this study was to investigate the effects of beta-cyclodextrin (beta-CD) & hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the solid-state chemical reactivity of the drug, quinapril, when amorphous samples are prepared by colyophilization of quinapril & each of these beta-CDs. For comparison, a physical mixture with beta-CD & colyophilized mixtures with trehalose & dextran were also prepared & subjected to a similar chemical stability test at 80 °C followed by HPLC analysis. Significant inhibition of degradation was observed only for colyophilized miscible mixtures with beta-CD & HP-beta-CD at molar ratios in excess of 1:1. Colyophilized mixtures with trehalose & dextran, shown to have phase separated, & the physical mixture with beta-CD exhibited no inhibiting effects. This suggests that specific molecular complexation is responsible for the significant inhibition by the beta-CDs. The tendency of quinapril to form molecular complexes in soln with the beta-CDs was measured by (1)H solution NMR, by estimating complexation constants from the chemical shift of specific groups on quinapril. Supporting evidence for solid-state complexation was provided by FTIR analysis. DSC & TSC measurements indicated that the beta-CDs do not have high enough glass transition temperatures to reduce reactivity by reducing molecular mobility.
Applications · 4 items
UsesAntihypertensive;Dopamine receptor agonist
UsesQuinapril is an angiotensin converting enzyme (ACE) inhibitor. Antihypertensive.
UsesQuinapril hydrochloride has been used as an angiotensin-converting enzyme (ACE) inhibitor to study its effects on renal tubular epithelial cell proliferation in human renal tubular epithelial cells. It has also been used as an ACE inhibitor to evaluate its effects on the expression of angiotensin II (AII) in patient-derived Atheroma samples.
General DescriptionQuinapril hydrochloride,(S)-[(S)-N-[(S)21-carboxy3-phenylpropyl]alanyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 1-ethyl ester hydrochloride(Acuretic), forms the diacid quinaprilate in thebody. It is more potent than captopril and equipotent to theactive form of enalapril.
DefinitionChEBI: Quinapril hydrochloride is a hydrochloride resulting from the reaction of equimolar amounts of quinapril and hydrogen chloride. A prodrug for quinaprilat hydrochloride (by hydrolysis of the ethyl ester to the corresponding carboxylic acid), it is used as an angiotensin-converting enzyme inhibitor (ACE inhibitor) for the treatment of hypertension and congestive heart failure. It has a role as an antihypertensive agent and an EC 3.4.15.1 (peptidyl-dipeptidase A) inhibitor. It contains a quinapril(1+).
