NAV

UCB7362

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Generic Name
UCB7362
DrugBank Accession Number
DB17096
Background

UCB7362 is an orally active plasmepsin X (PMX) inhibitor currently investigated for the treatment of malaria.1 Plasmepsins are aspartyl proteases produced by the malaria parasite Plasmodium falciparum, and PMX is considered to be essential for parasite egress and invasion.2 UCB7362 is estimated to achieve a significant reduction in asexual blood-stage parasites. It has shown high potency in biochemical (IC50 = 7 nM), in vitro (P. falciparum 3D7 lactate dehydrogenase growth inhibition assay IC50 = 10 nM), and in vivo (50 mg/kg dose in mice) studies.1

Type
Small Molecule
Groups
Investigational
Structure
Similar Structures
Weight
Average: 479.97
Monoisotopic: 479.1724174
Chemical Formula
C25H26ClN5O3
Synonyms
Not Available

Pharmacology

Indication

Not Available

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Pharmacodynamics

Not Available

Mechanism of action

Plasmepsins are aspartic acid proteases produced by malaria Plasmodium parasites. Several plasmepsins have been identified, and each one of them has a specific function. Plasmepsin X (PMX) controls parasite egress and invasion of erythrocytes and is essential during the red blood cell stages.2 UCB7362 binds to and inhibits PMX, disrupting the malaria parasite life cycle.1

TargetActionsOrganism
APlasmepsin X
inhibitor
binder
Plasmodium falciparum (isolate 3D7)
APlasmepsin X
inhibitor
binder
Plasmodium falciparum (isolate NF54)
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

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Not Available
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
Not Available
CAS number
Not Available
InChI Key
AWSRDDSRQUJMAJ-LCAJTWGOSA-N
InChI
InChI=1S/C25H26ClN5O3/c1-15-11-18(9-10-34-15)31-21(32)13-25(2,30-24(31)28)19-7-4-8-20(22(19)26)29-23(33)17-6-3-5-16(12-17)14-27/h3-8,12,15,18H,9-11,13H2,1-2H3,(H2,28,30)(H,29,33)/t15-,18-,25-/m0/s1
IUPAC Name
N-{2-chloro-3-[(4S)-2-imino-4-methyl-1-[(2S,4S)-2-methyloxan-4-yl]-6-oxo-1,3-diazinan-4-yl]phenyl}-3-cyanobenzamide
SMILES
C[C@H]1C[C@H](CCO1)N1C(=O)C[C@](C)(NC1=N)C1=C(Cl)C(NC(=O)C2=CC=CC(=C2)C#N)=CC=C1

References

General References
  1. Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T: Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362. J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336. Epub 2022 Oct 10. [Article]
  2. Nasamu AS, Polino AJ, Istvan ES, Goldberg DE: Malaria parasite plasmepsins: More than just plain old degradative pepsins. J Biol Chem. 2020 Jun 19;295(25):8425-8441. doi: 10.1074/jbc.REV120.009309. Epub 2020 May 4. [Article]
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
Caco2 permeability25Lowe, M. A., et al. J Med Chem. 2022; 65(20): 14121-14143.
pKa8.1Lowe, M. A., et al. J Med Chem. 2022; 65(20): 14121-14143.
Predicted Properties
PropertyValueSource
Water Solubility0.017 mg/mLALOGPS
logP3.47ALOGPS
logP3.13Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)14.51Chemaxon
pKa (Strongest Basic)5.1Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area118.31 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity140.99 m3·mol-1Chemaxon
Polarizability50.84 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Details1. Plasmepsin X
Kind
Protein
Organism
Plasmodium falciparum (isolate 3D7)
Pharmacological action
Yes
Actions
Inhibitor
Binder
General Function
During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775).
Specific Function
Aspartic-type endopeptidase activity
Gene Name
PMX
Uniprot ID
Q8IAS0
Uniprot Name
Plasmepsin X
Molecular Weight
65113.52 Da
References
  1. Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T: Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362. J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336. Epub 2022 Oct 10. [Article]
Details2. Plasmepsin X
Kind
Protein
Organism
Plasmodium falciparum (isolate NF54)
Pharmacological action
Yes
Actions
Inhibitor
Binder
General Function
During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074774). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074774). May process members of the EBL and Rh protein families (By similarity). Also cleaves apical membrane protein AMA1 (By similarity). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (By similarity).
Specific Function
Aspartic-type endopeptidase activity
Gene Name
PMX
Uniprot ID
W7JWW5
Uniprot Name
Plasmepsin X
Molecular Weight
65113.52 Da
References
  1. Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T: Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362. J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336. Epub 2022 Oct 10. [Article]

Drug created at November 10, 2022 00:41 / Updated at January 16, 2023 09:34