Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Immunology

Background:

• Leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT).
• BLT2 is implicated in pathologies such as diabetic wound healing, ophthalmic diseases, and colitis, highlighting its therapeutic potential.
• Development of in vivo pharmacological tools is crucial for validating BLT2 as a drug target.

Purpose of the Study:

• To discover and characterize a novel chemical probe for BLT2 agonism.
• To evaluate the potential of the novel probe as an orally applicable pharmacological tool for BLT2 target validation.
• To demonstrate the therapeutic effect of BLT2 activation in a relevant disease model.

Main Methods:

• Scaffold-hopping approach to identify novel BLT2 agonists.
• In vitro characterization of potency and selectivity.
• Assessment of physicochemical and pharmacokinetic (PK) properties.
• In vivo evaluation in a mouse model of psoriasis.

Main Results:

• Discovery of T-10430, a novel BLT2 agonist with high potency and a good selectivity profile.
• T-10430 possesses promising physicochemical and PK properties suitable for in vivo application.
• BLT2 activation using T-10430 demonstrated beneficial effects in a mouse model of psoriasis.

Conclusions:

• T-10430 is a potent and selective BLT2 agonist with favorable drug-like properties.
• This novel chemical probe can serve as a valuable pharmacological tool for validating BLT2 as a therapeutic target.
• The findings support the therapeutic potential of BLT2 activation in inflammatory conditions like psoriasis.