Blood-vessel-relaxing peptide (CHEMBL97431)

What this is

CHEMBL97431 is a short synthetic peptide designed in the early 1990s to block the endothelin-A receptor (ETA, gene name EDNRA) — a protein on blood vessel walls that, when activated by the hormone endothelin-1, triggers one of the most potent and prolonged vasoconstrictive responses known in the cardiovascular system. The compound belongs to a family of hexapeptide antagonists derived from the C-terminal region of endothelin-1 itself and was studied as a research tool to map which structural features of the peptide determine receptor binding and subtype selectivity (Cody and colleagues, Journal of Medicinal Chemistry, 1995).

The stored sequence LDILW (five residues in standard one-letter code) does not capture the complete chemistry of this compound: the actual molecule is N-terminally extended by a D-configured 3,3-diphenylalanine residue (D-Dip), and the entire N-terminus is acetylated. That D-Dip cap is critical to receptor affinity; without it, the remaining five residues alone bind with substantially lower potency.

History

The endothelin family of peptides was discovered in 1988 by Yanagisawa and colleagues, who isolated endothelin-1 from porcine aortic endothelial cells and identified it as the most potent vasoconstrictor then known. The existence of two receptor subtypes — ETA (now EDNRA) and ETB — was established in the early 1990s, alongside recognition that ETA drives the sustained vasoconstriction and smooth-muscle proliferation central to cardiovascular disease.

The hexapeptide antagonist series that includes CHEMBL97431 was developed at Parke-Davis in the early 1990s, based on the observation that the C-terminal six amino acids of endothelin-1 (His16–Leu17–Asp18–Ile19–Ile20–Trp21) retain biological activity at endothelin receptors and can be converted into antagonists by substituting the His16 position with bulky non-natural aromatic residues. The Cody 1995 paper (J Med Chem, 10.1021/jm00015a003) systematically explored structural modifications around the parent compound PD 142893 — Ac-D-Dip-Leu-Asp-Ile-Ile-Trp — to identify changes that selectively enhance affinity at ETA or ETB. CHEMBL97431 is one of the variants from that series, carrying a Leu at position 20 in place of the Ile20 present in PD 142893.

What it does

CHEMBL97431 binds to the ETA receptor and competes with endothelin-1 for the binding site, thereby blocking ET-1-driven vasoconstriction and downstream smooth-muscle signaling. In receptor binding assays it shows IC50 = 230 nM at the ETA receptor (ChEMBL CHEMBL97431). Additional binding and functional data across receptor subtypes were reported by Cody and colleagues (J Med Chem, 1995) as part of the systematic SAR characterization of this compound series.

Compared with the parent PD 142893, the Ile→Leu substitution at position 20 reduces receptor affinity, confirming that the branched side chain at that position contributes to tight packing in the binding site. The compound was used as a pharmacological tool to probe ETA/ETB selectivity and the structural determinants of endothelin receptor antagonism, not as a drug development candidate.

Evidence

• Human: No human studies. CHEMBL97431 is a research tool compound with no clinical development.
• Animal: No published in vivo data reported for this specific compound. The parent compound PD 142893 was characterized in vivo as a functional antagonist of ET-1-stimulated vasoconstriction.
• In vitro: Binding affinity at ETA IC50 = 230 nM (ChEMBL CHEMBL97431); additional receptor subtype and functional data in Cody and colleagues (J Med Chem, 1995).

No registered trials on ClinicalTrials.gov for CHEMBL97431 or its parent series.

Mechanism

ETA (EDNRA) is a class A G protein-coupled receptor expressed predominantly on vascular smooth muscle cells. On endothelin-1 binding, ETA couples through Gαq to activate phospholipase C, generating inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol; IP₃ releases Ca²⁺ from intracellular stores, triggering smooth-muscle contraction and promoting smooth-muscle cell proliferation — changes that contribute to vascular remodeling in disease states such as pulmonary arterial hypertension.

CHEMBL97431 acts as a competitive antagonist at ETA. The C-terminal Trp residue (corresponding to Trp21 of endothelin-1) is recognized as essential for receptor engagement across the hexapeptide series; the D-Dip cap at the N-terminus provides the bulk and conformational constraint that converts the agonist fragment into an antagonist. The Ile→Leu substitution at position 20 relative to PD 142893 reduces the hydrophobic contact area in the binding site, lowering affinity at ETA relative to the parent compound (Cody and colleagues, J Med Chem, 1995).

Known effects

• ETA receptor antagonism — binding IC50 = 230 nM (in vitro, ChEMBL CHEMBL97431)
• Reduced potency vs. parent PD 142893 — Ile20→Leu substitution lowers ETA binding affinity (Cody et al. 1995)
• No cell proliferation, vasomotor, or in vivo data reported for this specific compound

Regulatory status

• US: Not approved. Research compound only.
• EU: Not approved. Research compound only.
• WADA: Not listed. No performance-relevant use established.

Related peptides

The hexapeptide antagonist family this compound belongs to includes several closely related research ligands — most notably the parent compound PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), which is the most potent dual ETA/ETB antagonist in the Parke-Davis series. The broader endothelin receptor antagonist field ultimately produced approved small-molecule drugs — bosentan, ambrisentan, and macitentan — for pulmonary arterial hypertension; none of these are derived from the hexapeptide series.