Blood-vessel receptor probe (CHEMBL433349)

What this is

CHEMBL433349 is a short research-only peptide cataloged in the ChEMBL bioactivity database as a ligand of the endothelin A receptor (ETA, gene EDNRA). It is a five-residue peptide (Leu-Glu-Ile-Ile-Trp) belonging to the family of C-terminal endothelin fragment analogs that medicinal chemists explored in the 1990s as starting points for endothelin receptor antagonists. It is not a drug, not in clinical use, and not commercially available as a therapeutic — it is a structure-activity-relationship (SAR) data point used to map how the C-terminal region of endothelin-1 engages its receptors.

History

Endothelin-1 (ET-1) was identified in 1988 by Yanagisawa and colleagues as an endothelial-cell-derived vasoconstrictor peptide and is among the most potent vasoconstrictors known (reviewed in Davenport et al., Pharmacological Reviews, 2016). Two G-protein-coupled receptors for endothelin — ETA (EDNRA) and ETB (EDNRB) — were subsequently characterised, and intense medicinal-chemistry effort focused on truncating and modifying ET-1 to obtain receptor antagonists.

A central finding from that era was that the C-terminal hexapeptide of ET-1 (His16-Leu17-Asp18-Ile19-Ile20-Trp21) carries much of the receptor-binding information and that suitably modified analogs of this fragment can act as combined ETA/ETB antagonists. Cody and colleagues (Journal of Medicinal Chemistry, 1995) reported the structure-activity relationships around the lead peptide PD 142893 (Ac-DDip16-Leu-Asp-Ile-Ile-Trp21), a low-nanomolar combined ETA/ETB antagonist, and showed how individual substitutions within this C-terminal scaffold could shift potency and ETA-vs-ETB selectivity. CHEMBL433349 sits within this same chemical lineage of short C-terminal endothelin-derived peptides.

What it does

The endothelin A receptor (EDNRA) is the receptor most responsible for endothelin-1-driven vasoconstriction and vascular smooth-muscle growth (Davenport et al., 2016). Compounds that bind EDNRA with high affinity can — depending on their pharmacology — either mimic or block the actions of endogenous endothelin. CHEMBL433349 is recorded in ChEMBL as binding EDNRA with an IC50 of 21 nM in a radioligand displacement assay, placing it in the low-nanomolar affinity range typical of the C-terminal endothelin-peptide series. Whether this binding translates into functional agonism or antagonism in cellular assays is not specified by the dossier sources available here.

Evidence

• Human: No human studies. CHEMBL433349 is a research ligand with no clinical or in-vivo human data.
• Animal: No in-vivo animal data referenced in the dossier.
• In vitro: A single binding measurement (IC50 = 21 nM at EDNRA) is recorded in the ChEMBL database. The broader SAR framework around C-terminal endothelin pentapeptide/hexapeptide analogs is laid out by Cody and colleagues (1995, J Med Chem) for the lead compound PD 142893.

The peptidic endothelin antagonists in this chemical series — including the closely related hexapeptides PD 142893 and PD 145065 — were generally limited by poor proteolytic stability and short half-lives, which is why the field shifted toward non-peptide small-molecule ETA/ETB antagonists in subsequent decades.

Regulatory status

• US / EU: Not a drug. CHEMBL433349 has no marketing authorisation in any jurisdiction. It is a research compound only.
• Clinical class context: Approved endothelin receptor antagonists in clinical use today are small-molecule, non-peptidic compounds — examples include bosentan (a dual ETA/ETB antagonist, FDA-approved 2001 for pulmonary arterial hypertension) and ambrisentan (an ETA-selective antagonist) — not peptide ligands of the kind catalogued here.

Related peptides

This card sits within a broader set of endothelin-system entries on the platform; the cards for the endogenous endothelin peptides and other ChEMBL-derived EDNRA ligands are the natural neighbours, where they exist.