Ularitide

Identification

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Name
Ularitide
Accession Number
DB05034
Type
Small Molecule
Groups
Investigational
Description

Ularitide is a synthetic form of urodilatin, a naturally occurring human natriuretic peptide that is involved in regulating blood pressure and the excretion of water and sodium from the kidneys. Urodilatin is produced in the kidney and excreted into the urine, and thus exists in low levels naturally in the systemic blood circulation. When injected into the blood, ularitide appears to cause diuresis (urine output) and natriuresis (sodium excretion), as well as vasodilation. Ularitide is currently in Phase 2 development as a potential treatment for patients with acute decompensated heart failure (ADHF).

Structure
Thumb
Synonyms
  • Urodilatin ularitide
Categories
UNII
740Y5J48Z8
CAS number
118812-69-4
Weight
Average: 3505.926
Monoisotopic: 3503.683361186
Chemical Formula
C145H234N52O44S3
InChI Key
IUCCYQIEZNQWRS-DWWHXVEHSA-N
InChI
InChI=1S/C145H234N52O44S3/c1-11-72(6)112-137(238)171-60-106(208)172-73(7)113(214)177-86(40-41-103(146)205)122(223)190-95(63-198)116(217)170-61-108(210)175-88(51-70(2)3)114(215)169-62-109(211)176-100(133(234)187-92(56-104(147)206)127(228)193-97(65-200)130(231)186-91(54-77-27-16-13-17-28-77)126(227)180-82(31-20-45-163-142(153)154)119(220)189-94(139(240)241)55-78-36-38-79(204)39-37-78)68-243-244-69-101(134(235)185-90(53-76-25-14-12-15-26-76)115(216)168-58-105(207)167-59-107(209)174-80(29-18-43-161-140(149)150)117(218)182-87(42-50-242-10)123(224)188-93(57-110(212)213)128(229)181-85(124(225)196-112)34-23-48-166-145(159)160)195-132(233)99(67-202)194-131(232)98(66-201)192-120(221)83(32-21-46-164-143(155)156)178-118(219)81(30-19-44-162-141(151)152)179-125(226)89(52-71(4)5)184-129(230)96(64-199)191-121(222)84(33-22-47-165-144(157)158)183-135(236)102-35-24-49-197(102)138(239)74(8)173-136(237)111(148)75(9)203/h12-17,25-28,36-39,70-75,80-102,111-112,198-204H,11,18-24,29-35,40-69,148H2,1-10H3,(H2,146,205)(H2,147,206)(H,167,207)(H,168,216)(H,169,215)(H,170,217)(H,171,238)(H,172,208)(H,173,237)(H,174,209)(H,175,210)(H,176,211)(H,177,214)(H,178,219)(H,179,226)(H,180,227)(H,181,229)(H,182,218)(H,183,236)(H,184,230)(H,185,235)(H,186,231)(H,187,234)(H,188,224)(H,189,220)(H,190,223)(H,191,222)(H,192,221)(H,193,228)(H,194,232)(H,195,233)(H,196,225)(H,212,213)(H,240,241)(H4,149,150,161)(H4,151,152,162)(H4,153,154,163)(H4,155,156,164)(H4,157,158,165)(H4,159,160,166)/t72-,73-,74-,75+,80-,81-,82-,83-,84-,85-,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,111-,112-/m0/s1
IUPAC Name
(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-{[(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,49S,52R)-52-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-{[(2S)-1-[(2S)-2-[(2S,3R)-2-amino-3-hydroxybutanamido]propanoyl]pyrrolidin-2-yl]formamido}-5-carbamimidamidopentanamido]-3-hydroxypropanamido]-4-methylpentanamido]-5-carbamimidamidopentanamido]-5-carbamimidamidopentanamido]-3-hydroxypropanamido]-3-hydroxypropanamido]-49-benzyl-28-[(2S)-butan-2-yl]-31,40-bis(3-carbamimidamidopropyl)-19-(2-carbamoylethyl)-34-(carboxymethyl)-16-(hydroxymethyl)-22-methyl-10-(2-methylpropyl)-37-[2-(methylsulfanyl)ethyl]-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecaazacyclotripentacontan-4-yl]formamido}-3-carbamoylpropanamido]-3-hydroxypropanamido]-3-phenylpropanamido]-5-carbamimidamidopentanamido]-3-(4-hydroxyphenyl)propanoic acid
SMILES
CC[C@H](C)[C@@H]1NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CSSC[C@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)O

Pharmacology

Indication

Investigated for use/treatment in congestive heart failure.

Pharmacodynamics
Not Available
Mechanism of action

Ularitide, a synthetic form of urodilatin, belongs to the family of natriuretic peptides. Urodilatin stimulates the intracellular guanylyl cyclase as the intracellular domain of the natriuretic peptide receptor A (NPR-A), the enzyme that catalyzes the conversion of GTP to cGMP [7]. Activation of cGMP-dependent protein kinase inhibits sodium reabsorption via an amiloride-sensitive channel and furthermore results in smooth muscle relaxation via a decrease in intracellular Ca2+ concentration. Thus, ularitide is an intrarenal paracrine regulator of sodium and water homeostasis.

TargetActionsOrganism
UAtrial natriuretic peptide receptor 1Not AvailableHumans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirUlaritide may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AcarboseUlaritide may increase the excretion rate of Acarbose which could result in a lower serum level and potentially a reduction in efficacy.
AceclofenacUlaritide may increase the excretion rate of Aceclofenac which could result in a lower serum level and potentially a reduction in efficacy.
AcemetacinThe therapeutic efficacy of Ularitide can be decreased when used in combination with Acemetacin.
AcetaminophenUlaritide may increase the excretion rate of Acetaminophen which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Ularitide which could result in a higher serum level.
AclidiniumUlaritide may increase the excretion rate of Aclidinium which could result in a lower serum level and potentially a reduction in efficacy.
AcrivastineUlaritide may increase the excretion rate of Acrivastine which could result in a lower serum level and potentially a reduction in efficacy.
AcyclovirUlaritide may increase the excretion rate of Acyclovir which could result in a lower serum level and potentially a reduction in efficacy.
Albutrepenonacog alfaUlaritide may increase the excretion rate of Albutrepenonacog alfa which could result in a lower serum level and potentially a reduction in efficacy.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Carstens J, Gronbaek H, Larsen HK, Pedersen EB, Vilstrup H: Effects of urodilatin on natriuresis in cirrhosis patients with sodium retention. BMC Gastroenterol. 2007 Jan 26;7:1. [PubMed:17257428]
  2. Hirsch JR, Meyer M, Forssmann WG: ANP and urodilatin: who is who in the kidney. Eur J Med Res. 2006 Oct 27;11(10):447-54. [PubMed:17107879]
External Links
PubChem Compound
16132416
PubChem Substance
175426934
ChemSpider
17289074
ChEMBL
CHEMBL2103920
Wikipedia
Atrial_natriuretic_peptide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnTreatmentCongestive Heart Failure (CHF)1
2CompletedPreventionAcute Renal Failure (ARF) / Renal Dysfunction / The Mortality Rate1
3CompletedTreatmentAcute Decompensated Heart Failure (ADHF)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 Solubility0.15 mg/mLALOGPS
logP-0.94ALOGPS
logP-29ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.13ChemAxon
pKa (Strongest Basic)12.68ChemAxon
Physiological Charge5ChemAxon
Hydrogen Acceptor Count63ChemAxon
Hydrogen Donor Count60ChemAxon
Polar Surface Area1593.12 Å2ChemAxon
Rotatable Bond Count82ChemAxon
Refractivity930.43 m3·mol-1ChemAxon
Polarizability355.05 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7865
Blood Brain Barrier-0.9853
Caco-2 permeable-0.7214
P-glycoprotein substrateSubstrate0.9271
P-glycoprotein inhibitor INon-inhibitor0.748
P-glycoprotein inhibitor IINon-inhibitor0.9108
Renal organic cation transporterNon-inhibitor0.8007
CYP450 2C9 substrateNon-substrate0.7788
CYP450 2D6 substrateNon-substrate0.806
CYP450 3A4 substrateSubstrate0.5775
CYP450 1A2 substrateNon-inhibitor0.8273
CYP450 2C9 inhibitorNon-inhibitor0.7765
CYP450 2D6 inhibitorNon-inhibitor0.8577
CYP450 2C19 inhibitorNon-inhibitor0.7557
CYP450 3A4 inhibitorNon-inhibitor0.6163
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9646
Ames testNon AMES toxic0.7993
CarcinogenicityNon-carcinogens0.809
BiodegradationNot ready biodegradable0.8598
Rat acute toxicity3.1462 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9167
hERG inhibition (predictor II)Inhibitor0.6047
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Cyclic peptides / Tyrosine and derivatives / Arginine and derivatives / Phenylalanine and derivatives / Asparagine and derivatives / Leucine and derivatives / N-acyl-L-alpha-amino acids / Proline and derivatives / Serine and derivatives / Alpha amino acid amides
show 27 more
Substituents
Polypeptide / Cyclic alpha peptide / Tyrosine or derivatives / Arginine or derivatives / Phenylalanine or derivatives / Asparagine or derivatives / Leucine or derivatives / Proline or derivatives / N-acyl-alpha-amino acid / N-acyl-l-alpha-amino acid
show 53 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein kinase activity
Specific Function
Receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis. Has guanylate ...
Gene Name
NPR1
Uniprot ID
P16066
Uniprot Name
Atrial natriuretic peptide receptor 1
Molecular Weight
118918.11 Da

Drug created on October 21, 2007 16:23 / Updated on June 04, 2019 06:14