Discovery of Long-Acting Bifunctional Compounds with Muscarinic M3 and Histamine H1 Receptor Antagonism for the Treatment of Rhinitis

Abstract Rhinitis is a heterogeneous inflammatory condition of the upper airway mucosa. Chronic symptoms are often refractory to first-line intranasal antihistamines and corticosteroids, particularly in mixed and nonallergic phenotypes. Add-on anticholinergic treatment alleviates rhinorrhea but is hampered by short duration of action and multiple daily administrations. We describe here unique heterobifunctional M3/H1 dual antagonists designed for once-daily intranasal treatment. By tuning a novel bifunctional scaffold combining a diarylsulfone-based muscarinic antagonist with various antihistamine chemotypes, potent dual-acting ligands were developed with negligible systemic exposure and prolonged residence in nasal mucosa (>24 h). Lead compounds 30/34 (M3KB = 120/122 nM, H1KB = 4.60/6.72 nM, respectively) suppressed capsaicin-induced nonallergic rhinitis symptoms in guinea pigs similarly to comparators (ipratropium/olopatadine), while in ovalbumin-induced allergic rhinitis in mice, 34 achieved equivalent symptom control to dexamethasone/ipratropium and inhibited alarmin cytokines (IL-33/TSLP). These findings support further development of dual-targeting antimuscarinic/antihistamine agents as long-acting therapeutics for refractory rhinitis.