TRPM8 BLOCKERS: RATIONAL DESIGN OF NOVEL POTENT AND SELECTIVE SMALL MOLECULE CHEMICAL SERIES FOR NEUROPATHIC PAIN RELIEF

Aramini Andrea, Bianchini Gianluca and Marcello Allegretti

Discovery Department, R&D Dompé SpA, L’Aquila, Italy

Abstract

Transient receptor potential (TRP) channels constitute a large family of ion channels involved in different cellular functions [1]. In humans, TRPs are expressed on many tissues and are considered key mediators of sensory transduction being involved in taste recognition and temperature sensing. Within the TRP family, TRP melastatin-8 (TRPM8) is activated by moderate cold and exogenous “cooling-mimetic” compounds, such as menthol and icilin [2]. TRPM8 is widely expressed on peripheral terminals of sensory neurons. Thus, TRPM8 has generated great interest for its role in neuropathic pain, in particular in cold allodynia, bladder sensing and more recently in ophthalmology disorder [3].

We recently reported a small molecular weight TRPM8 Blocker (DFL 23448), for the treatment of urology disorders [4]. DFL23448 is topically administered due to poor oral exposure in rats, attributable to elimination through glucoronidation mechanisms. SAR studies using the pharmacophore features extracted from the first series of TRPM8 blockers aimed to improve its metabolic stability.

We identified a new chemical class of TRPM8 blockers. DFL23588 was selected due to its high selectivity and potency (IC₅₀ = 32 nM), and its pK profile suitable to oral neuropathic pain treatment.

REFERENCES

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[4] Mistretta M., Aramini A., et al. JPET (2016), 356, 200-211.