Discovery and pharmacological evaluation of a novel series of chromenopyrazole-based GPR55 modulators in an androgen-driven model of female metabolic dysfunction

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GPR55 is a lipid-responsive G-protein-coupled receptor implicated in metabolic regulation, but its characterization has been limited by the poor selectivity and pathway bias of classical ligands. To obtain more reliable chemical tools, we revisited the chromenopyrazole scaffold and prepared a focused series of derivatives to refine GPR55 pharmacology. In vitro profiling identified compound A as a selective lysophosphatidylinositol (LPI)-dependent positive allosteric modulator, whereas compounds 16 and 23 displayed dual orthosteric/allosteric activity. All derivatives showed clean GPR55 engagement with no detectable cannabinoid receptor type 2 activity, highlighting the improved selectivity of this scaffold. The biological relevance of these pharmacological profiles was assessed in a preclinical model of androgen-driven metabolic dysfunction reproducing key features of the metabolic phenotype observed in women with polycystic ovary syndrome (PCOS). In this model, compound A improved body weight regulation, glucose tolerance, and insulin sensitivity, while lowering serum cholesterol and triglycerides. Hepatic parameters followed a similar pattern, with reduced steatosis, macrophage infiltration, and early fibrotic remodeling. Compounds 16 and 23 produced broadly comparable benefits despite their distinct modes of GPR55 engagement, suggesting convergence on shared downstream pathways buffering metabolic stress. Hepatic GPR55 expression increased under steatotic and inflammatory conditions but normalized after treatment, supporting the potential advantage of allosteric enhancement of endogenous LPI signaling. Overall, these findings identify chromenopyrazoles as a selective GPR55-modulating scaffold with the potential to mitigate metabolic and hepatic dysfunction in models reflecting key features of PCOS.