Omapatrilat

Identification

Name
Omapatrilat
Accession Number
DB00886  (APRD00443)
Type
Small Molecule
Groups
Investigational
Description

Omapatrilat is an investigational drug that inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). NEP inhibition results in elevated natriuretic peptide levels, promoting natriuresis, diuresis, vasodilation, and reductions in preload and ventricular remodeling. This drug from BMS was not approved by the FDA due to angioedema safety concerns.

Structure
Thumb
Synonyms
  • Omapatrilate
External IDs
BMS 186716 / BMS-186716 / BMS-186716-01
International/Other Brands
Vanlev
Categories
UNII
36NLI90E7T
CAS number
167305-00-2
Weight
Average: 408.53
Monoisotopic: 408.117749609
Chemical Formula
C19H24N2O4S2
InChI Key
LVRLSYPNFFBYCZ-VGWMRTNUSA-N
InChI
InChI=1S/C19H24N2O4S2/c22-17(15(26)11-12-5-2-1-3-6-12)20-13-9-10-27-16-8-4-7-14(19(24)25)21(16)18(13)23/h1-3,5-6,13-16,26H,4,7-11H2,(H,20,22)(H,24,25)/t13-,14-,15-,16-/m0/s1
IUPAC Name
(4S,7S,10aS)-5-oxo-4-[(2S)-3-phenyl-2-sulfanylpropanamido]-octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid
SMILES
[H][C@]12CCC[C@H](N1C(=O)[C@H](CCS2)NC(=O)[C@@H](S)CC1=CC=CC=C1)C(O)=O

Pharmacology

Indication

For the treatment of hypertension.

Pharmacodynamics

Omapatrilat is used to treat hypertension. Vasopeptidase inhibitor that simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Omapatrilat lowers blood pressure by inhibiting the action of the angiotensin converting enzyme (ACE), which causes blood vessels to constrict. But unlike other drugs, omapatrilat also inhibits another enzyme known as neutral endopeptidase (NEP), which helps blood vessels relax. Omapatrilat demonstrated greater reduction in blood pressure than the ACE inhibitor lisinopril in individuals with salt-sensitive hypertension who typically do not respond well to ACE inhibitors.

Mechanism of action

Omapatrilat binds to both angiotensin converting enzyme and neutral endopeptidase. This results in a decrease renin-angiotensin-aldosterone production and increase natriuretic peptidase circulation.

TargetActionsOrganism
UAngiotensin-converting enzymeNot AvailableHuman
ANeprilysinNot AvailableHuman
Absorption

The absolute oral bioavailability of omapatrilat is 20% to 30% and the absorption is not affected by food intake.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Side effects include hyperkalemia, cough, hypotension, increased SrCr, and dizziness. Dizziness, diarrhea, vision disturbance, hypotension and angioedema

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe risk or severity of hyperkalemia can be increased when Omapatrilat is combined with Acebutolol.
AceclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Aceclofenac is combined with Omapatrilat.
AcemetacinThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acemetacin is combined with Omapatrilat.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Omapatrilat.
AgmatineThe risk or severity of hyperkalemia can be increased when Omapatrilat is combined with Agmatine.
Agrostis gigantea pollenThe risk or severity of adverse effects can be increased when Omapatrilat is combined with Agrostis gigantea pollen.
Agrostis stolonifera pollenThe risk or severity of adverse effects can be increased when Omapatrilat is combined with Agrostis stolonifera pollen.
AlclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Alclofenac is combined with Omapatrilat.
AlfuzosinAlfuzosin may increase the hypotensive activities of Omapatrilat.
AliskirenThe risk or severity of hypotension, hyperkalemia, and nephrotoxicity can be increased when Aliskiren is combined with Omapatrilat.
Food Interactions
Not Available

References

General References
  1. Rabkin SW, Klassen SS: Omapatrilat enhances adrenomedullin's reduction of cardiomyocyte cell death. Eur J Pharmacol. 2007 May 21;562(3):174-82. Epub 2007 Feb 8. [PubMed:17343842]
External Links
KEGG Drug
D01970
PubChem Compound
656629
PubChem Substance
175426852
ChemSpider
570983
BindingDB
50073120
ChEBI
135660
ChEMBL
CHEMBL289556
Wikipedia
Omapatrilat

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0769 mg/mLALOGPS
logP2.15ALOGPS
logP2.06ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area86.71 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity106.68 m3·mol-1ChemAxon
Polarizability41.8 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9567
Blood Brain Barrier-0.9219
Caco-2 permeable-0.7793
P-glycoprotein substrateSubstrate0.7377
P-glycoprotein inhibitor INon-inhibitor0.7782
P-glycoprotein inhibitor IINon-inhibitor0.9778
Renal organic cation transporterNon-inhibitor0.8896
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateNon-substrate0.5745
CYP450 1A2 substrateNon-inhibitor0.8791
CYP450 2C9 inhibitorNon-inhibitor0.8218
CYP450 2D6 inhibitorNon-inhibitor0.8781
CYP450 2C19 inhibitorNon-inhibitor0.7666
CYP450 3A4 inhibitorInhibitor0.5854
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.93
Ames testNon AMES toxic0.8423
CarcinogenicityNon-carcinogens0.9497
BiodegradationNot ready biodegradable0.9922
Rat acute toxicity2.0641 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9918
hERG inhibition (predictor II)Non-inhibitor0.624
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
N-acyl-alpha amino acids and derivatives / Piperidinecarboxylic acids / Benzene and substituted derivatives / Fatty amides / Tertiary carboxylic acid amides / Secondary carboxylic acid amides / Lactams / Alkylthiols / Azacyclic compounds / Thiohemiaminal derivatives
show 8 more
Substituents
Alpha-dipeptide / N-acyl-alpha amino acid or derivatives / Alpha-amino acid or derivatives / Piperidinecarboxylic acid / Monocyclic benzene moiety / Fatty amide / Piperidine / Benzenoid / Fatty acyl / Tertiary carboxylic acid amide
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent...
Gene Name
ACE
Uniprot ID
P12821
Uniprot Name
Angiotensin-converting enzyme
Molecular Weight
149713.675 Da
References
  1. Azizi M, Massien C, Michaud A, Corvol P: In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor. Hypertension. 2000 Jun;35(6):1226-31. [PubMed:10856268]
  2. Ferdinand KC: Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor. J Clin Hypertens (Greenwich). 2001 Sep-Oct;3(5):307-12. [PubMed:11588409]
  3. Heudi O, Ramirez-Molina C, Marshall P, Amour A, Peace S, McKeown S, Abou-Shakra F: Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and omapatrilat. J Pept Sci. 2002 Nov;8(11):591-600. [PubMed:12487427]
  4. Neal B, MacMahon S, Ohkubo T, Brnabic A, Tonkin A: Effects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease. J Renin Angiotensin Aldosterone Syst. 2002 Dec;3(4):270-6. [PubMed:12584671]
  5. Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad MM: Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol. 1999 Dec;34(6):782-90. [PubMed:10598120]
Details
2. Neprilysin
Kind
Protein
Organism
Human
Pharmacological action
Yes
General Function
Zinc ion binding
Specific Function
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptide...
Gene Name
MME
Uniprot ID
P08473
Uniprot Name
Neprilysin
Molecular Weight
85513.225 Da
References
  1. Intengan HD, Schiffrin EL: Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension. 2000 Jun;35(6):1221-5. [PubMed:10856267]
  2. Azizi M, Massien C, Michaud A, Corvol P: In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor. Hypertension. 2000 Jun;35(6):1226-31. [PubMed:10856268]
  3. McClean DR, Ikram H, Garlick AH, Richards AM, Nicholls MG, Crozier IG: The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure. J Am Coll Cardiol. 2000 Aug;36(2):479-86. [PubMed:10933361]
  4. Troughton RW, Rademaker MT, Powell JD, Yandle TG, Espiner EA, Frampton CM, Nicholls MG, Richards AM: Beneficial renal and hemodynamic effects of omapatrilat in mild and severe heart failure. Hypertension. 2000 Oct;36(4):523-30. [PubMed:11040230]
  5. Burrell LM, Droogh J, Man in't Veld O, Rockell MD, Farina NK, Johnston CI: Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hypertens. 2000 Oct;13(10):1110-6. [PubMed:11041166]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:52