Blood-vessel-relaxing peptide (CHEMBL265116)

What this is

This is a short experimental peptide built to block one of the body's strongest blood-vessel-constricting signals. The full compound (ChEMBL CHEMBL265116) is an N-acetylated hexapeptide whose last five residues are the standard amino acids L-D-F-I-W (leucine–aspartate–phenylalanine–isoleucine–tryptophan) shown in the stored sequence; an additional non-standard residue (a D-diphenylalanine analog) sits between the acetyl cap and the leucine and is not encoded in the one-letter sequence. It was made and tested as part of a 1990s academic medicinal-chemistry program at Parke-Davis that mapped how the C-terminal tail of endothelin-1 — the natural ligand for the endothelin A and B receptors — could be shrunk down into a small peptide antagonist (Cody et al., J. Med. Chem., 1995). It is a research tool ligand, not a drug; it has no approved use and no clinical development history of its own.

History

The compound comes from the Parke-Davis (Warner-Lambert) endothelin SAR campaign led by Wayne Cody, which produced the lead hexapeptide PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp; PMID 7636842). That campaign asked a focused question: how small can a peptide get and still block endothelin receptors? It started from the observation that the C-terminal hexapeptide of endothelin-1 (His16-Leu17-Asp18-Ile19-Ile20-Trp21) carries enough of the binding information to drive receptor antagonism on its own. CHEMBL265116 is one of the many analogs reported in the series Cody and colleagues used to explore which side chains in that hexapeptide could be swapped without losing affinity (Cody et al., 1995). The work fed into a broader literature that eventually produced clinically used small-molecule endothelin receptor antagonists (bosentan, ambrisentan, macitentan) — but those are non-peptide drugs developed by other groups; this peptide series was a structural and pharmacological probe, not a clinical candidate.

What it does

In binding assays, the compound competes with endothelin-1 for the endothelin A receptor (EDNRA / ETᴀ) — a G-protein-coupled receptor expressed on vascular smooth muscle that, when activated by endothelin-1, drives long-lasting vasoconstriction and smooth-muscle proliferation (Davenport et al., Pharmacol. Rev., 2016). The structured bioactivity recorded in ChEMBL for CHEMBL265116 is an EDNRA IC50 of 160 nM, which puts it in the low-to-mid nanomolar range typical of the truncated-hexapeptide series. The card lists EDNRA as the only assigned target; selectivity against the related endothelin B receptor (EDNRB) is not part of the stored record for this specific analog.

Mechanism

The endothelin receptors ETᴀ and ETᴃ are Class A GPCRs whose endogenous agonists are the 21-residue endothelins (ET-1, ET-2, ET-3). Antagonist design from the peptide side has consistently shown that the C-terminal Trp21 of endothelin-1 is critical — it docks into a tryptophan-adjacent pocket in the receptor transmembrane core, and modifications at or near that residue are dominant determinants of both affinity and ETᴀ-vs-ETᴃ selectivity (Cody et al., 1995; Sakamoto et al., J. Med. Chem., 1996, PMID 8784429). The PD 142893 series, of which this compound is a member, retains the acidic Asp and the C-terminal Trp of the parent endothelin hexapeptide while varying the hydrophobic core and the N-cap; the N-terminal acetyl group and the bulky D-aromatic residue at the second position are conserved features of the scaffold that protect against aminopeptidase trimming and reinforce the binding pose (Cody et al., 1995). Neither the acetyl cap nor the D-diphenylalanine analog is visible in the one-letter sequence LDFIW; the stored sequence is the bare standard-residue backbone.

Evidence

• In vitro: EDNRA binding IC50 = 160 nM, sourced from ChEMBL bioactivity record CHEMBL265116. The parent series (PD 142893 and close analogs) was characterized in radioligand competition assays against ETᴀ and ETᴃ across mammalian tissues (Cody et al., J. Med. Chem., 1995).
• Animal: No in vivo data are recorded for this specific analog in the dossier. The parent PD 142893 was profiled in vivo as a research tool antagonist (Cody et al., 1995).
• Human: No human studies. This is a ChEMBL research ligand with no clinical development.

Regulatory status

• Clinical/approved use: None. CHEMBL265116 has no recorded development phase in ChEMBL and no INN/USAN name. It is a research-grade compound only.
• Drug class context: The clinically approved endothelin receptor antagonists for pulmonary arterial hypertension (bosentan, ambrisentan, macitentan) are non-peptide small molecules from independent discovery programs (Davenport et al., Pharmacol. Rev., 2016). This peptide does not belong to that approved-drug set.
• WADA: Not on the WADA prohibited list under any peptide-class entry; it is a research ligand without therapeutic use.

Open questions

• Selectivity of this specific analog (LDFIW core) for EDNRA versus EDNRB is not documented in the dossier; the parent PD 142893 was a combined ETᴀ/ETᴃ antagonist (Cody et al., 1995), so subtype preference here is unresolved without further reading of the original SAR table.
• Proteolytic stability, plasma half-life, and route-of-exposure profiles are not characterized for this analog in any source available in the dossier.
• No structural data (co-crystal or cryo-EM with EDNRA) exist for this specific peptide; structural understanding of antagonist binding at endothelin receptors comes from the related ETᴃ inverse-agonist IRL2500 complex (Nagiri et al., Nat. Struct. Mol. Biol., 2019) and from small-molecule antagonist structures, not from this compound.

Related peptides

The compound belongs to the C-terminal-hexapeptide endothelin-antagonist family that descends from the parent endothelin-1 sequence and the Cody/Parke-Davis SAR campaign (PD 142893 and its analogs). Other ChEMBL peptide ligands targeting EDNRA exist in the platform catalog but are not cross-linked here because their pep-IDs are not verified in this dossier.