General
Preferred name
RAMIPRIL
Synonyms
HOE-498 ()
Tritace ()
Altace ()
Carasel ()
NSC-758933 ()
Ecator ()
Triatec ()
HOE 498 ()
Ramace ()
Lopace ()
Delix ()
Hopace ()
Cardace ()
Vesdil ()
Corpril ()
Ramipres ()
C09AA05 ()
Unipril ()
Pramace ()
Ranace ()
Ramipril-d5 ()
P&D ID
PD000559
CAS
126613-39-6
1028843-43-7
87333-19-5
1132661-86-9
Tags
prodrug
natural product
drug
available
Approved by
FDA
First approval
1991
Drug Status
approved
Drug indication
Congestive heart failure
Enzyme Inhibitor (angiotensin-converting)
Coronavirus Disease 2019 (COVID-19)
Antihypertensive
Max Phase
Phase 4
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
ROE 60% of the parent drug and its metabolites are eliminated in the urine with the remaining 40% eliminated in the feces.[FDA Label] The drug eliminated in the feces represents both absorbed drug and drug eliminated through biliary excretion although the proportion of these has not been determined. Less than 2% of drug is eliminated in the urine unchanged.
MOA Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. [T116] As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT1R) and angiotensin receptor II (AT2R) occurs. AT1R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. [T116] These include Gq coupling to the inositol triphosphate pathway, activation of phospholipases C, A2, and D which contribute to eicosanoid production, activation of Ca2+-dependent and MAP kinases, Gi and G12/13, and eventual activation of the Jak/STAT pathway leading to cell growth and production of extracellular matrix components. AT1R activation also leads to increased activity of membrane-bound NADH/NADPH oxidase which contributes to production of reactive oxygen species. Decreased activation of this receptor mediates the renoprotective, antihypertensive, and cardioprotective effects of ramipril by reducing inflammation and vasoconstriction. AT2R acts in opposition to the effects of AT1R by activating phosphotyrosine phosphatases which inhibit MAP kinases, inhibiting Ca2+ channel opening, and stimulating cGMP and nitric oxide production leading to vasodilation. [T116] These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT2R although the bulk of its effect is mediated by MasR. ACE is also responsible for the breakdown of bradykinin. [T116] The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.
INDICATION For the management of mild to severe hypertension. May be used to reduce cardiovascular mortality following myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart failure within a few days following myocardial infarction. [FDA Label] To reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events. May be used to slow the progression of renal disease in individuals with hypertension, diabetes mellitus and microalubinuria or overt nephropathy. [T116]
METABOLISM Hepatic metabolism accounts for 75% of total ramipril metabolism.[FDA Label] 25% of hepatic metabolism produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism converts ramipril to ramiprilat. Other metabolites, diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, are inactive.
ABSORPTION The extent of absorption is at least 50-60%.[FDA Label]. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.
MOA Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. [T116] As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT1R) and angiotensin receptor II (AT2R) occurs. ; ; AT1R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. [T116] These include Gq coupling to the inositol triphosphate pathway, activation of phospholipases C, A2, and D which contribute to eicosanoid production, activation of Ca2+-dependent and MAP kinases, Gi and G12/13, and eventual activation of the Jak/STAT pathway leading to cell growth and production of extracellular matrix components. AT1R activation also leads to increased activity of membrane-bound NADH/NADPH oxidase which contributes to production of reactive oxygen species. Decreased activation of this receptor mediates the renoprotective, antihypertensive, and cardioprotective effects of ramipril by reducing inflammation and vasoconstriction.; ; AT2R acts in opposition to the effects of AT1R by activating phosphotyrosine phosphatases which inhibit MAP kinases, inhibiting Ca2+ channel opening, and stimulating cGMP and nitric oxide production leading to vasodilation. [T116] These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT2R although the bulk of its effect is mediated by MasR.; ; ACE is also responsible for the breakdown of bradykinin. [T116] The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.; ;
TOXICITY Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes.[A174280] Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase. ; ; There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area.; ; No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test.; ; No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure.; ; LD50 10 g/kg (rat).[MSDS]; LD50 10.5 g/kg (mouse).[MSDS]; LD50 1 g/kg (dog).[MSDS];
DESCRIPTION Pro-drug, transformed in the liver to its active metabolite (drug) ramiprilat (GtoPdb)
PHARMACODYNAMICS Ramipril is an ACE inhibitor similar to benazepril, fosinopril and quinapril. [T116] It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. Ramiprilat confers blood pressure lowing effects by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing increased vasodilation and decreased blood pressure.
HALF-LIFE Plasma concentrations of ramiprilat decline in a triphasic manner.[FDA Label] Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase is 9-18 hours, which is thought to represent clearance of free drug. The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation. The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs.
TOXICITY Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes.[A174280] Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase. There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area. No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test. No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure. LD50 10 g/kg (rat).[MSDS] LD50 10.5 g/kg (mouse).[MSDS] LD50 1 g/kg (dog).[MSDS]
DESCRIPTION Potent furin inhibitor (Tocris Bioactive Compound Library)
DESCRIPTION Non-peptide, competitive angiotensin-converting enzyme (ACE) inhibitor (Tocriscreen Plus)
Compound Sets
25
Cayman Chemical Bioactives
15558
25425
ChEMBL Approved Drugs
CHEMBL1168
ChEMBL Drugs
CHEMBL1168
Drug Repurposing Hub
DrugBank
DB00178
DrugBank Approved Drugs
DB00178
DrugCentral
2356
DrugCentral Approved Drugs
2356
DrugMAP
DM2R68E
DMO2TYL
DrugMAP Approved Drugs
DM2R68E
Enamine BioReference Compounds
Guide to Pharmacology
6339
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL1168
Mcule NIBR MoA Box Subset
MCULE-8858912367
MedChem Express Bioactive Compound Library
HY-B0279
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
Ramipril(Altace)
TargetMol Bioactive Compound Library
T1645
The Spectrum Collection
Tocris Bioactive Compound Library
5250
Tocriscreen Plus
5250
External IDs
52
Properties
(calculated by RDKit )
Molecular Weight
416.23
Hydrogen Bond Acceptors
5
Hydrogen Bond Donors
2
Rotatable Bonds
9
Ring Count
3
Aromatic Ring Count
1
cLogP
2.38
TPSA
95.94
Fraction CSP3
0.61
Chiral centers
5.0
Largest ring
6.0
QED
0.6
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target Type
Enzymes
Pathway
Endocrinology/Hormones
Apoptosis
Metabolic Enzyme/Protease
Target
ACE
Angiotensin-converting Enzyme (ACE)
ACE,RAAS
Primary Target
Angiotensin-Converting Enzyme
MOA
Inhibitor
Angiotensin-I Converting Enzyme (ACE) Inhibitors
angiotensin converting enzyme inhibitor
Member status
member
Indication
hypertension
Therapeutic Class
Antihypertensive Agents
Antiviral Agents
Source data