Identification

Name
Lacidipine
Accession Number
DB09236
Type
Small Molecule
Groups
Approved, Investigational
Description

Lacidipine is a lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity. Due to its long duration of action, lacidipine does not lead to reflex tachycardia [1]. It displays specificity in the vascular smooth muscle, where it acts as an antihypertensive agent to dilate peripheral arterioles and reduce blood pressure. Compared to other dihydropyridine calcium antagonists, lacidipine exhibits a greater antioxidant activity which may confer potentially beneficial antiatherosclerotic effects [4]. Lacidipine is a highly lipophilic molecule that interacts with the biological membranes. Through radiotracer analysis, it was determined that lacidipine displays a high membrane partition coefficient leading to accumulation of the drug in the membrane and slow rate of membrane washout [3]. When visualized by small-angle X-ray diffraction with angstrom resolution to examine its location within the membranes, lacidipine was found deep within the membrane's hydrocarbon core [3]. These results may explain the long clinical half-life of lacidipine [3].

In randomised, well-controlled trials, administration of daily single-dose lacidipine ranging from 2-6 mg demonstrated comparable antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor) [1]. It is available as once-daily oral tablets containing 2 or 4 mg of the active compound commonly marketed as Lacipil or Motens. It is not currently FDA-approved.

Structure
Thumb
Synonyms
  • Lacidipino
International/Other Brands
Caldine (Boehringer Ingelheim) / Lacimen (GlaxoSmithKline) / Lacipil (GSK) / Motens (Boehringer Ingelheim)
Categories
UNII
260080034N
CAS number
103890-78-4
Weight
Average: 455.551
Monoisotopic: 455.230787787
Chemical Formula
C26H33NO6
InChI Key
GKQPCPXONLDCMU-CCEZHUSRSA-N
InChI
InChI=1S/C26H33NO6/c1-8-31-24(29)21-16(3)27-17(4)22(25(30)32-9-2)23(21)19-13-11-10-12-18(19)14-15-20(28)33-26(5,6)7/h10-15,23,27H,8-9H2,1-7H3/b15-14+
IUPAC Name
3,5-diethyl 4-{2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl}-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
CCOC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C)C(=O)OCC

Pharmacology

Indication

Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors [6].

Pharmacodynamics

acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure [6].

Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers) [6].

Mechanism of action

By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx [2]. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor [5]. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel [5].

Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation [4]. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques [4].

TargetActionsOrganism
AVoltage dependent L type calcium channel
antagonist
Human
Absorption

Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing [6]. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers [2].

Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver [6].

Volume of distribution
Not Available
Protein binding

Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein [6].

Metabolism

Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity [2].

Route of elimination

Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine [6].

Half life

The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state [6].

Clearance
Not Available
Toxicity

There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended [6].

Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively [MSDS].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Lacidipine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Lacidipine.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may increase the hypotensive activities of Lacidipine.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Lacidipine is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Lacidipine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Lacidipine.
5-androstenedioneThe metabolism of Lacidipine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Lacidipine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Lacidipine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Lacidipine.
Food Interactions
Not Available

References

Synthesis Reference

Lacidipine synthesis: C. Semeraro et al., DE 3529997; eidem, U.S. Patent 4,801,599 (1986, 1989 both to Glaxo).

General References
  1. McCormack PL, Wagstaff AJ: Lacidipine: a review of its use in the management of hypertension. Drugs. 2003;63(21):2327-56. [PubMed:14524737]
  2. Lee CR, Bryson HM: Lacidipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of hypertension. Drugs. 1994 Aug;48(2):274-96. [PubMed:7527328]
  3. Herbette LG, Gaviraghi G, Tulenko T, Mason RP: Molecular interaction between lacidipine and biological membranes. J Hypertens Suppl. 1993 Mar;11(1):S13-9. [PubMed:8387105]
  4. Ishii N, Matsumura T, Shimoda S, Araki E: Anti-atherosclerotic potential of dihydropyridine calcium channel blockers. J Atheroscler Thromb. 2012;19(8):693-704. Epub 2012 May 17. [PubMed:22653165]
  5. Cerbai E, Giotti A, Mugelli A: Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes. Br J Pharmacol. 1997 Feb;120(4):667-75. doi: 10.1038/sj.bjp.0700951. [PubMed:9051306]
  6. Lacidipine Summary of Product Characteristics [Link]
External Links
KEGG Drug
D04657
PubChem Compound
5311217
PubChem Substance
310265140
ChemSpider
4470736
ChEBI
135737
ChEMBL
CHEMBL460291
Wikipedia
Lacidipine
ATC Codes
C08CA09 — Lacidipine
MSDS
Download (78.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers4
2CompletedTreatmentAngina Pectoris1
3CompletedTreatmentHigh Blood Pressure (Hypertension)1
4CompletedTreatmentHigh Blood Pressure (Hypertension)2
4CompletedTreatmentHypertension,Essential / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableHigh Blood Pressure (Hypertension)1
Not AvailableTerminatedNot AvailableHigh Blood Pressure (Hypertension)1

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
PropertyValueSource
Water Solubility0.00224 mg/mLALOGPS
logP5.18ALOGPS
logP4.19ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)19.47ChemAxon
pKa (Strongest Basic)-6.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area90.93 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity129.91 m3·mol-1ChemAxon
Polarizability49.74 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00fr-0000900000-2964b6b69c71aeda6088
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0169400000-672099fb92e2023950eb

Taxonomy

Description
This compound belongs to the class of organic compounds known as cinnamic acid esters. These are compound containing an ester derivative of cinnamic acid.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Cinnamic acids and derivatives
Sub Class
Cinnamic acid esters
Direct Parent
Cinnamic acid esters
Alternative Parents
Tricarboxylic acids and derivatives / Dihydropyridinecarboxylic acids and derivatives / Styrenes / Fatty acid esters / Vinylogous amides / Enoate esters / Amino acids and derivatives / Enamines / Dialkylamines / Azacyclic compounds
show 4 more
Substituents
Cinnamic acid ester / Dihydropyridinecarboxylic acid derivative / Tricarboxylic acid or derivatives / Styrene / Dihydropyridine / Fatty acid ester / Monocyclic benzene moiety / Fatty acyl / Hydropyridine / Benzenoid
show 21 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...

Components:
References
  1. Cerbai E, Giotti A, Mugelli A: Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes. Br J Pharmacol. 1997 Feb;120(4):667-75. doi: 10.1038/sj.bjp.0700951. [PubMed:9051306]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Ziviani L, Da Ros L, Squassante L, Milleri S, Cugola M, Iavarone LE: The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects. Br J Clin Pharmacol. 2001 Feb;51(2):147-52. [PubMed:11259986]
  2. Lacidipine Summary of Product Characteristics [Link]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Lacidipine Summary of Product Characteristics [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Lacidipine Summary of Product Characteristics [Link]

Drug created on October 23, 2015 10:33 / Updated on November 05, 2018 17:49