Orally active small molecule antagonists of the human protease-activated receptor 2 developed for potential treatment of inflammatory diseases, metabolic syndrome & cancer


The Technology
Distributed widely throughout the body, the G protein coupled receptor, protease-activated receptor 2 (PAR2) has been implicated as a pro-inflammatory mediator in chronic inflammatory diseases including arthritis, psoriasis, inflammatory bowel disease, pancreatitis, and cardiovascular disease. PAR2 has also been reported as anti-inflammatory and protective in some conditions such as gastric ulcer and asthma.

PAR2 activation has also been linked to proliferation, metastasis and angiogenesis in many cancers including cancers of the stomach, colon, breast and pancreas. In this context, small-molecule modulators of PAR2 are of potential interest as a new class of anti-inflammatory and pro-inflammatory, and/or anti-proliferative or proliferative agents.

Discovered in the 1990s, there are four PAR family members (designated PAR1, PAR2, PAR3 and PAR4). A defining feature of these receptors is their irreversible activation by proteases; mainly serine. In contrast with other GPCRs, PARs are not activated in vivo by binding of a soluble endogenous extracellular ligand but, instead, are triggered by proteases which cleave extracellularly to the N-terminus of the receptor. This cleavage exposes a new amino terminus (tethered ligand; TL) that then binds intramolecularly to activate the receptor (self-activation) and induces intracellular signal transduction. PAR2 is emerging as a viable therapeutic target in a diverse range of diseases.

Short synthetic peptides corresponding to the newly exposed N-terminal tethered ligand can activate three of the four known PARs (PAR1, 2 and 4 and possibly PAR3) in the absence of proteases, and such PAR activating peptides (PAR-APs) have served as tools for agonist/antagonist development. In fact much of the evidence for involvement of PARs in diseases initially relied upon use of PAR-APs, often of low potency and uncertain selectivity.

Use of PAR-APs is particularly informative in settings where more than one PAR is expressed and activated by the same protease, such as in human platelets where both PAR1 and PAR4 are expressed and activated by thrombin. There is now extensive knockout data in support of essential roles for PAR2 in disease.

Most PAR antagonists and agonists identified to date have been peptides corresponding to, or derived from, the TL sequence unique to each PAR. Using structure-activity approaches, PAR2-APs have been designed to mimic the natural TL sequence from the human (SLIGKV) and mouse (SLIGRL) receptors. Although some potent PAR2-APs have been developed, the typically poor bioavailability of these molecules is a major limitation for in vivo studies.

To improve drug-like properties, our research team has developed novel classes of non-peptidic PAR2 agonists and antagonists from hexapeptides. Using intracellular Ca2+ release as a measure of PAR2 activation, agonist GB110 (EC50 0.28μM) was discovered. GB110 selectively activates PAR2 expressed by a range of cell lines. It is equipotent with the most potent synthetic peptide agonists reported for PAR2 as well as being selective for PAR2 over PAR1, and has no effect on PAR1 activation by thrombin or on intracellular Ca2+ release in cells desensitized to PAR2 activation.

Subsequently, our research team has identified a novel PAR2 antagonist, GB88 derived from the agonist GB110. It was the first PAR2 antagonist to reversibly inhibit activation of this receptor by endogenous ligands (e.g. trypsin, tryptase), synthetic peptides (e.g. SLIGRL-NH2, 2f-LIGRLO-NH2) and non-peptide (e.g. GB110) agonists at low concentrations (IC50~1μM). Furthermore, GB88 is stable in serum, orally active and has been investigated for PAR2 modulation in vivo in a range of animal models of human inflammatory and proliferative diseases. Administered orally GB88 inhibits rat paw oedema elicited by PAR2 agonists but not PAR1 agonists, and substantially inhibits collagen-induced arthritis in rats. The research team recently developed more potent, more PAR2-selective, chemically stable and orally bioavailable small molecule compounds that modulate PAR2, and have been evaluating them as agonists or antagonists in multiple human cells for pro-inflammatory, anti-inflammatory or proliferative activities. A range of novel agonists and antagonists have been identified with greater potency than GB110 or GB88 (EC50 or IC50 between 100 nM to 1µM) in multiple human cells (both cultured and primary cell types). Computer-assisted molecular modeling has been used to further refine antagonist series’ using homology models developed via sequence alignment, X-ray crystallography and receptor mutations. The table below shows a series of PAR2 antagonists that are being explored in a range of disease models to exploit their therapeutic potential.

Selected PAR antagonists (GB series, AY series and KW series)
We have demonstrated potent anti-inflammatory and anti-obesity activity for PAR2-selective antagonists in rat models of, for example, TNBS-induced colitis, collagen-induced arthritis and diet-induced obesity, metabolic and cardiovascular dysfunction including cardiac fibrosis.

Key Benefits

- Novel small molecules
- Orally active
- Effective in models of acute and chronic inflammation, IBD and obesity
- Selective and potent
- Novel target and unique mechanism of action.


PAR2 antagonists have the potential to be developed as first-in-class treatments for:
• Arthritis
• Inflammatory Bowel Disease
• Psoriasis
• Obesity, diabetes and cardiovascular disease
• Cancer (breast, lung, colon, stomach, prostate)
• Pancreatitis.
There is also the potential to develop PAR2 agonists to treat asthma, fibrosis and gastric ulcers. There are no PAR2 modulators on the market so this is a first-in-class opportunity.

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