PL37   Click here for help

GtoPdb Ligand ID: 7896

Synonyms: 19-IIIa [3] | Debio 0827 [1] | Debio-0827
Compound class: Synthetic organic
Comment: PL37 is an investigational, orally available, dual pro-drug inhibitor of neprilysin (a.k.a. neutral endopeptidase or NEP; MME) and aminopeptidase N (APN; ANPEP) [3]. NEP and APN are enkephalin catabolising enzymes (or enkephalinases). Dual ENKephalinase inhibitors such as this one have been ascribed the acronym DENK inhibitor (or DENKi).
PL37 is the non-stereo enantiomer of compound 15 in patent US8247609 [4]. Such dual inhibitors are suggested as a novel mechanism for the control of central and peripheral pain [5], via inhibition of enzymatic degradation of endogenous enkephalins. Such agents could replace the use of opiate analgesics.
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 20
Topological polar surface area 192.85
Molecular weight 518.16
XLogP 4.08
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CSCCC(CSSCC(C(=O)NCC(=O)OC(OC(=O)OCC)C)Cc1ccccc1)N
Isomeric SMILES CSCCC(CSSCC(C(=O)NCC(=O)OC(OC(=O)OCC)C)Cc1ccccc1)N
InChI InChI=1S/C22H34N2O6S3/c1-4-28-22(27)30-16(2)29-20(25)13-24-21(26)18(12-17-8-6-5-7-9-17)14-32-33-15-19(23)10-11-31-3/h5-9,16,18-19H,4,10-15,23H2,1-3H3,(H,24,26)
InChI Key BJCNUZJDFWFVBY-UHFFFAOYSA-N
References
1. González-Rodríguez S, Pevida M, Roques BP, Fournié-Zaluski MC, Hidalgo A, Menéndez L, Baamonde A. (2009)
Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors.
Neurosci Lett, 465 (3): 285-9. [PMID:19765404]
2. Menéndez L, Hidalgo A, Meana A, Poras H, Fournié-Zaluski MC, Roques BP, Baamonde A. (2008)
Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin.
Eur J Pharmacol, 596 (1-3): 50-5. [PMID:18692494]
3. Poras H, Bonnard E, Dangé E, Fournié-Zaluski MC, Roques BP. (2014)
New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment.
J Med Chem, 57 (13): 5748-63. [PMID:24927250]
4. Roques B, Fournie-Zaluski M-C. (2012)
Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase N inhibitors.
Patent number: US8247609 B2. Assignee: Pharamleads. Priority date: 25/10/2005. Publication date: 21/08/2012.
5. Tesfaye S. (2016)
PL37: a new hope in the treatment of painful diabetic neuropathy?.
Pain Manag, 6 (2): 129-32. [PMID:26984197]
6. Thibault K, Elisabeth B, Sophie D, Claude FZ, Bernard R, Bernard C. (2008)
Antinociceptive and anti-allodynic effects of oral PL37, a complete inhibitor of enkephalin-catabolizing enzymes, in a rat model of peripheral neuropathic pain induced by vincristine.
Eur J Pharmacol, 600 (1-3): 71-7. [PMID:18938155]