Blood-vessel-narrowing blocker (CHEMBL405599)

What this is

This card describes a research peptide indexed in the ChEMBL bioactivity database (CHEMBL405599) that was published as part of a structure–activity study on endothelin receptor antagonists. The compound is a short peptide built around the C-terminal "RDIIW" sequence — a five-residue stretch (Arg-Asp-Ile-Ile-Trp) that descends from the C-terminus of endothelin-1 (see /card/pep-04474), the body's most potent natural vasoconstrictor. The full compound as registered in ChEMBL carries an N-terminal acetyl cap and a modified hydrophobic residue ahead of the Arg, which the stored five-letter sequence (RDIIW) does not show; the parent series was reported by Cody and colleagues (J Med Chem, 1995). It is a laboratory tool used to probe the pharmacology of the endothelin A receptor (ETA / EDNRA), not a marketed drug or a clinical candidate.

History

The endothelin family was discovered in 1988, and within a few years it was established that the C-terminal hexapeptide of endothelin-1 — His-Leu-Asp-Ile-Ile-Trp (positions 16–21) — is the minimum fragment that still binds and acts at the endothelin receptors. That observation kicked off a search for short, "C-terminal-mimic" peptides that could block, rather than activate, the receptors. Cody and colleagues at Parke-Davis described the lead compound of this series, Ac-DDip-Leu-Asp-Ile-Ile-Trp (PD 142893), a hexapeptide combined ETA/ETB antagonist, in Journal of Medicinal Chemistry in 1995 (Cody et al., 1995, doi:10.1021/jm00015a003). CHEMBL405599 is one of the analogs reported in that SAR series, in which the residue at position 16 was varied and the C-terminal Leu-Asp-Ile-Ile-Trp pharmacophore was preserved.

What it does

In radioligand binding assays drawn from the same SAR paper and indexed in ChEMBL, this compound binds the endothelin A receptor in rabbit renal vascular smooth muscle membranes with an IC50 of 4.0 nM, and it inhibits endothelin-1–stimulated arachidonic acid release in those cells with an IC50 of 14 nM (Cody et al., J Med Chem 1995). Against the endothelin B receptor it is much weaker at the human subtype (IC50 ≈ 590 nM in transfected CHO cells) but more potent against the rat ETB receptor in cerebellar membranes (IC50 ≈ 10 nM) — a species/subtype split that is well known for this chemical series. In practical terms, it is a nanomolar antagonist of the endothelin receptor system in cellular assays, with a preference for ETA over human ETB.

Mechanism

Endothelin A and endothelin B are G protein–coupled receptors that, when activated by endothelin-1, drive vasoconstriction (predominantly ETA on vascular smooth muscle) and a mixture of nitric oxide–mediated dilation, ET-1 clearance, and pro-fibrotic signalling (predominantly ETB on endothelium and lung). C-terminal hexapeptide antagonists of the PD-142893 class — to which CHEMBL405599 belongs — occupy the orthosteric peptide pocket that the native C-terminus of endothelin-1 engages, displacing the agonist and blocking signalling. The 5-letter sequence stored on this card (RDIIW) omits the N-terminal acetyl cap and the modified position-16 residue present in the registered ChEMBL structure; both modifications matter for the compound's potency in the original paper.

Evidence

• Human: No human trials. This is a research-grade peptide reported in a medicinal-chemistry SAR study and indexed in ChEMBL; it has no clinical development history.
• Animal: No standalone in vivo studies attributed to this specific analog in the available sources. Lead compounds from the same series (PD 142893 and follow-on pseudopeptides such as PD 156252) were profiled in vivo, but those data do not transfer to this analog.
• In vitro: Binding and functional antagonism characterized in rabbit renal vascular smooth muscle (ETA-like) and at recombinant/native ETA and ETB preparations, with values noted in "What it does" (Cody et al., J Med Chem 1995).

Known effects

• ETA receptor binding — Nanomolar IC50 in rabbit renal vascular smooth muscle (ChEMBL-indexed from Cody 1995).
• Functional ET-1 antagonism — Blocks ET-1–stimulated arachidonic acid release in the same cell preparation (IC50 ≈ 14 nM, Cody 1995).
• ETB receptor binding — Active at rat ETB; markedly weaker at human ETB, consistent with the species split reported for this chemical class.

Regulatory status

• US / EU: Not a drug. CHEMBL405599 is a research compound listed in the ChEMBL bioactivity database; it is not FDA- or EMA-approved and is not in clinical development.
• Clinical context for the target class: Three small-molecule endothelin receptor antagonists — bosentan, ambrisentan and macitentan — are approved for pulmonary arterial hypertension. None of them is a peptide, and none of them is this compound; they are listed here only to anchor the EDNRA target's clinical relevance.

Related peptides

• Endothelin-1 (pep-04474) — the endogenous 21-residue agonist of EDNRA/EDNRB whose C-terminal hexapeptide (HLDIIW) is the structural template for the RDIIW series.
• EDNRA ligand CHEMBL319719 — LAIIW (pep-10324) — sister 5-mer entry from the same SAR class, reported IC50 = 35 nM.
• EDNRA ligand CHEMBL433349 — LEIIW (pep-10326) — another 5-mer congener in the same series, reported IC50 = 21 nM.