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Identification
NameOmapatrilat
Accession NumberDB00886  (APRD00443)
TypeSmall Molecule
GroupsInvestigational
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 Identifiers
  • BMS 186716
  • BMS-186716
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
VanlevNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII36NLI90E7T
CAS number167305-00-2
WeightAverage: 408.53
Monoisotopic: 408.117749609
Chemical FormulaC19H24N2O4S2
InChI KeyLVRLSYPNFFBYCZ-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[[email protected]](N1C(=O)[[email protected]](CCS2)NC(=O)[C@@H](S)CC1=CC=CC=C1)C(O)=O
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentDipeptides
Alternative Parents
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
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Lactam
  • Alkylthiol
  • Hemithioaminal
  • Thioether
  • Azacycle
  • Organoheterocyclic compound
  • Dialkylthioether
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Organosulfur compound
  • Organic oxide
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of hypertension.
PharmacodynamicsOmapatrilat 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 actionOmapatrilat binds to both angiotensin converting enzyme and neutral endopeptidase. This results in a decrease renin-angiotensin-aldosterone production and increase natriuretic peptidase circulation.
Related Articles
AbsorptionThe absolute oral bioavailability of omapatrilat is 20% to 30% and the absorption is not affected by food intake.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySide effects include hyperkalemia, cough, hypotension, increased SrCr, and dizziness. Dizziness, diarrhea, vision disturbance, hypotension and angioedema
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot 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 vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.
Gene Name:
ACE
Uniprot ID:
P12821
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 ]
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 peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of at...
Gene Name:
MME
Uniprot ID:
P08473
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 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23