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Lisinopril hydrate (MK-521), an enalapril analog, is a potent angiotensin-converting enzyme (ACE) inhibitor used in treatment of hypertension, congestive heart failure, and heart attacks, and also in preventing renal and retinal complications of diabetes. Lisinopril significantly reduces left ventricular (LV) end-diastolic pressure (EDP), pulmonary capillary wedge pressure (PCWP) and end-diastolic stress, addition of atenolol to Lisinopril further reduces EDP and PCWP. Lisinopril is a structural homologue of enalaprilat, differing only in the second amino acid side chain.
Physicochemical Properties
| Molecular Formula | C21H35N3O7 |
| Molecular Weight | 441.52 |
| Exact Mass | 441.247 |
| Elemental Analysis | C, 57.13; H, 7.99; N, 9.52; O, 25.37 |
| CAS # | 83915-83-7 |
| Related CAS # | Lisinopril;76547-98-3;Lisinopril-d5;1356905-39-9 |
| PubChem CID | 5362119 |
| Appearance | White to off-white solid powder |
| Density | 1.251 g/cm3 |
| Boiling Point | 666.4ºC at 760 mmHg |
| Melting Point | 160ºC (Decomposes) |
| Flash Point | 356.9ºC |
| Index of Refraction | -45 ° (C=1, 0.25mol/L Zinc Acetate Buffer) |
| LogP | 2.264 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 29 |
| Complexity | 550 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | C1C[C@H](N(C1)C(=O)[C@H](CCCCN)N[C@@H](CCC2=CC=CC=C2)C(=O)O)C(=O)O |
| InChi Key | CZRQXSDBMCMPNJ-ZUIPZQNBSA-N |
| InChi Code | InChI=1S/C21H31N3O5.2H2O/c22-13-5-4-9-16(19(25)24-14-6-10-18(24)21(28)29)23-17(20(26)27)12-11-15-7-2-1-3-8-15/h1-3,7-8,16-18,23H,4-6,9-14,22H2,(H,26,27)(H,28,29)2*1H2/t16-,17-,18-/m0../s1 |
| Chemical Name | ((S)-1-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate |
| Synonyms | MK-521; MK521; MK 521; Lisinopril dihydrate; Lisinopril dihydrate; 83915-83-7; Renacor; Lisinopril (dihydrate); MK-521; CHEBI:6503; E7199S1YWR; Prinivil; Qbrelis; Ranolip; Renacor |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Angiotensin-converting enzyme (ACE) |
| ln Vitro | The enzyme that changes angiotensin I (ATI) into angiotensin II (ATII) is called angiotensin-converting enzyme (ACE), and lisinopri dihydrate is a strong and competitive inhibitor of this enzyme. Renin-angiotensin-aldosterone system (RAAS) constituent ATII controls blood pressure. Lisinopril is prescribed to treat hypertension, symptomatic congestive heart failure, to prolong survival following myocardial infarction in some patients, and to stop the advancement of renal disease in hypertensive patients with diabetes, microalbuminuria, or overt nephropathy [1][2]. |
| ln Vivo | Lisinopril treated SHR rats has significantly raised total cholesterol levels compared to untreated spontaneously hypertensive rats (SHR) rats (+27%), but not compared to lisinopril treated Wistar Kyoto rats (WKY) rats. Lisinopril is a long-acting angiotensin-converting enzyme inhibitor which blocks the renin-angiotensin system (RAS) and reduces systemic blood pressure in rats. Lisinopril reduces the hydroxyproline level and inhibits accumulation of collagens in the pulmonary tissue of the treatment group (paraquat + lisinopril) and per-treatment group (lisinopril + paraquat) in rats. Lisinopril results in preserved ultrafiltration volume (UF), glucose reabsorption (D 1 /D 0 glucose) and peritoneal thickness in rats. Lisinopril (0.2 mg/kg twice a day for 10 days) protects the cell membrane integrity and lessens free radical-induced oxidant stress in guinea pig hearts. |
| Enzyme Assay | Isothermal titration calorimetry[1] ITC experiments were performed using a MCS microcalorimeter. This instrument has been described in detail by Wiseman et al. The reference cell was filled with water, and the instrument was calibrated using standard electrical pulses. A circulating water bath was used to stabilize the temperature. The instrument was allowed to equilibrate overnight. All solutions were thoroughly degassed by stirring under vacuum before use. Solutions of s-ACE were titrated with 10 identical 10 μl injections at 6 min-intervals. The injection syringe, on which a paddle is mounted, stirred the solutions at 300 rpm, ensuring immediate mixing. Concentrations of the protein used for the titrations were in the range of 3.5–16.4 μM, while concentrations of the inhibitors were 0.6–3.0 mM (l-Asp-l-Phe) and 0.2–0.5 mM (lisinopril, captopril and enalaprilat). All the experiments in this study were conducted at a NaCl concentration of 300 mM and in at least two different buffers. Dilution experiments were performed by identical injections of s-ACE inhibitor into the cell containing only buffer. The peaks of the thermograms were integrated and the heat produced by the binding reaction was calculated as the difference between the reaction heat and the corresponding dilution heat. |
| Cell Assay | Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.[3] |
| Animal Protocol | In this study, 2 groups from each of the 3 rat strains had their hearts irradiated (8 Gy X 5 fractions). One irradiated group was treated with the ACE-inhibitor lisinopril, and a separate group in each strain served as nonirradiated controls. Radiation reduced cardiac end diastolic volume by 9-11% and increased thickness of the interventricular septum (11-16%) and left ventricular posterior wall (14-15%) in all 3 strains (5-10 rats/group) after 120 days. Lisinopril mitigated the increase in posterior wall thickness. Mitochondrial function was measured by the Seahorse Cell Mitochondrial Stress test in peripheral blood mononuclear cells (PBMC) at 90 days. Radiation did not alter mitochondrial respiration in PBMC from BN or SSBN6. However, maximal mitochondrial respiration and spare capacity were reduced by radiation in PBMC from SS rats (p=0.016 and 0.002 respectively, 9-10 rats/group) and this effect was mitigated by lisinopril (p=0.04 and 0.023 respectively, 9-10 rats/group). Taken together, these results indicate injury to the heart by radiation in all 3 strains of rats, although the SS rats had greater susceptibility for mitochondrial dysfunction. Lisinopril mitigated injury independent of genetic background.[4] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Lisinopril is 6-60% orally bioavailable with an average of 25% bioavailability. Lisinopril reaches a Cmax of 58ng/mL with a Tmax of 6-8h. Lisinopril's absorption is not affected by food. Lisinopril is entirely eliminated exclusively in the urine. The apparent volume of distribution of lisinopril is 124L. A 30kg child has a typical clearance of 10L/h, which increases with renal function. The mean renal clearance of lisinopril in healthy adult males is 121mL/min. Steady state is attained after two daily doses (every 24 hours) in healthy volunteers. The drug is not metabolized but is eliminated via the kidneys. In dogs, lisinopril's bioavilability ranges from 24-50% with peak levels occurring approximately 4 hours after dosing. Lisinopril is distributed poorly into the CNS. It is unknown if it is distributed into maternal milk, but it does cross the placenta. Following oral administration of Prinivil, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large inter-subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to about 16 percent in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers. For more Absorption, Distribution and Excretion (Complete) data for LISINOPRIL (9 total), please visit the HSDB record page. Metabolism / Metabolites Lisinopril is not metabolized and is excreted as the unchanged drug. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Biological Half-Life Lisinopril has an effective half life of accumulation of 12.6h and a terminal half life of 46.7h. The plasma half-life controlling accumulation during chronic administration is 12-13 hr and the absorbed drug is eliminated via glomerular filtration. The accumulation half-life averages 12.6 hours despite a terminal serum half-life of approximately 40 hours /in healthy volunteers/. Upon multiple dosing, lisinopril exhibits an effective half-life of 12 hours. |
| Toxicity/Toxicokinetics |
Toxicity Summary IDENTIFICATION AND USE: Lisinopril is angiotensin-converting enzyme (ACE) inhibitor, antihypertensive and cardiotonic agent. HUMAN EXPOSURE AND TOXICITY: The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Marked hypotension may occur in patients with congestive heart failure-potential for myocardial infarction or stroke in those with acute myocardial infarction or ischemic cardiovascular or cerebrovascular disease. Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice or hepatitis; may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including lisinopril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring. Hyperkalemia can develop, especially in those with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration. Sensitivity reactions, including anaphylactoid reactions and angioedema (including laryngeal edema, tongue edema), are potentially fatal. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. ANIMAL STUDIES: There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg per kg per day or for 92 weeks to male and female mice at doses up to 135 mg per kg per day. Lisinopril treatment in male rats resulted in a marked decrease in sperm density, sperm motility and zona pellucida penetration. Acrosome reaction by spermatozoa obtained from drug-treated animals was significantly lower when compared with spermatozoa from normal animals. The developmental toxicity of lisinopri have been tested in mice and rabbits. In mice, the incidence of resorptions increased at all dosage levels. No treatment-related adverse effects were found on litter sizes of live fetuses and mean fetal weights. In rabbits, mean fetal weights were normal, although ossification was retarded at all dosage levels. External, skeletal and visceral examinations did not reveal any teratogenic potential at any dosage level in mice and rabbits. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow. There were 1781 dogs exposed to lisinopril and 156 that became symptomatic. The most common clinical signs included: lethargy (24%), tachycardia (18%), vomiting (14%) and hypotension (13%). Of the 98 cats, 7 were symptomatic with 29% hypertensive 29% tachycardic and 29% vomiting. Interactions Potential pharmacologic interaction (additive hyperkalemic effect). Includes potassium-sparing diuretics, potassium supplements, and other drugs that can increase serum potassium. The manufacturer states that lisinopril should be used cautiously (with frequent monitoring of serum potassium), if at all, with potassium supplements or salt substitutes containing potassium. Potential pharmacologic interaction (increased hypoglycemic effect), especially during initial weeks of combined treatment /of lisinopril and antidiabetic agents/ and in patients with renal impairment. Potential pharmacologic interaction (additive hyperkalemic effect). Includes potassium-sparing diuretics, potassium supplements, and other drugs that can increase serum potassium. The manufacturer states that lisinopril should be used cautiously (with frequent monitoring of serum potassium), if at all, with potassium supplements or salt substitutes containing potassium. Potential pharmacologic interaction (decreased antihypertensive effect) when lisinopril is used concomitantly concurrently with nonsteroidal anti-inflammatory agents (NSAIAs). Potential pharmacologic interaction (decreased renal function) when lisinopril is used concomitantly with NSAIAs in patients with impaired renal function. For more Interactions (Complete) data for LISINOPRIL (14 total), please visit the HSDB record page. |
| References |
[1]. Andujar-Sanchez, M., V. Jara-Perez, and A. Camara-Artigas, Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method. FEBS Lett, 2007. 581(18): p. 3449-54. [2]. Song, J.C. and C.M. White, Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet, 2002. 41(3): p. 207-24. |
| Additional Infomation |
Therapeutic Uses Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiotonic Agents Prinivil is indicated for the treatment of hypertension in adult patients and pediatric patients 6 years of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. ... Prinivil may be administered alone or with other antihypertensive agents /Included in US product labeling/ Prinivil is indicated to reduce signs and symptoms of heart failure in patients who are not responding adequately to diuretics and digitalis /Included in US product labeling/ Prinivil is indicated for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. /Included in US product label/ For more Therapeutic Uses (Complete) data for LISINOPRIL (6 total), please visit the HSDB record page. Drug Warnings /BOXED WARNING/ WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Prinivil as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Milk of lactating rats contains radioactivity following administration of (14)C lisinopril. It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, discontinue nursing or discontinue Prinivil. Antihypertensive effects and safety of Prinivil have been established in pediatric patients aged 6 to 16 years. No relevant differences between the adverse reaction profile for pediatric patients and adult patients were identified. Safety and effectiveness of Prinivil have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 sq m. Adverse effects reported in greater than 1% of patients receiving lisinopril for the management of heart failure and more frequently than with placebo include dizziness, hypotension, headache, diarrhea, chest pain, nausea, abdominal pain, rash, and upper respiratory tract infection. For more Drug Warnings (Complete) data for LISINOPRIL (23 total), please visit the HSDB record page. Pharmacodynamics Lisinopril is an angiotensin converting enzyme inhibitor used to treat hypertension, heart failure, and myocardial infarction. Lisinopril is not a prodrug, and functions by inhibition of angiotensin converting enzyme as well as the renin angiotensin aldosterone system. It has a wide therapeutic index and a long duration of action as patients are generally given 10-80mg daily. |
Solubility Data
| Solubility (In Vitro) |
H2O : ~33.33 mg/mL (~75.49 mM) DMSO : ~1 mg/mL (~2.26 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (113.25 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2649 mL | 11.3245 mL | 22.6490 mL | |
| 5 mM | 0.4530 mL | 2.2649 mL | 4.5298 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2649 mL |