ACS Medicinal Chemistry Letters· 2026Q1
Discovery of Pyrazolopyrimidines as Potent and Orally Bioavailable MRGPRX2 Antagonists
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- Q1SCImago
- 2026year
Short summary
A novel pyrazolopyrimidine scaffold yields potent, orally bioavailable MRGPRX2 antagonists, with INCB187175 showing strong preclinical efficacy in inhibiting mast cell degranulation and in vivo activation.
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Key points
- A pyrazolopyrimidine scaffold was developed as a potent MRGPRX2 antagonist.
- INCB187175 (compound 23) achieved nanomolar activity in cellular assays and good oral exposure.
- INCB187175 inhibited MRGPRX2-mediated degranulation in primary human mast cells.
- INCB187175 demonstrated in vivo efficacy in suppressing mast cell activation.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract The Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates IgE-independent mast cell activation and is implicated in pseudoallergic drug reactions, chronic urticaria, atopic dermatitis, rosacea, neurogenic inflammation, and other mast cell-mediated disorders. Herein, we report the discovery of a pyrazolopyrimidine series as potent and orally bioavailable MRGPRX2 antagonists. A scaffold hybridization strategy, supported by systematic structure–activity relationship studies, yielded antagonists with nanomolar activity in both Gq/IP1 and beta-arrestin cellular assays. Addressing solubility limitations and CYP inhibition liability, while maintaining favorable pharmacokinetic properties, led to the identification of INCB187175 (compound 23), which exhibits good cellular potency and robust oral exposure across preclinical species. Importantly, functional activity was validated in a beta-hexosaminidase release assay using primary human mast cells, demonstrating potent inhibition of MRGPRX2-mediated degranulation. This activity translated in vivo, where INCB187175 effectively suppressed mast cell activation in an Evans blue extravasation assay. These findings establish the pyrazolopyrimidine chemotype as a promising scaffold for inhibition of MRGPRX2 signaling and support INCB187175 as a compelling drug candidate for further development in mast cell-mediated diseases.
The authors' abstract, as published at the source. ACS Medicinal Chemistry Letters, 2026 · DOI ↗
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ImmunologyImmunology and Microbiology