Discovery of Novel TRPM8 Blockers Suitable for the Treatment of Somatic and Ocular Painful Conditions: A Journey through pKa and LogD Modulation

Transient receptor potential melastatin 8 (TRPM8) is crucially involved in pain modulation and perception, and TRPM8 antagonists have been proposed as potential therapeutic approaches for pain treatment. Previously, we developed two TRPM8 antagonists and proposed them as drug candidates for topical and systemic pain treatment. Here, we describe the design and synthesis of these two TRPM8 antagonists (27 and 45) and the rational approach of modulation/replacement of bioisosteric chemical groups, which allowed us to identify a combination of narrow ranges of pKa and LogD values that were crucial to ultimately optimize their potency and metabolic stability. Following the same approach, we then pursued the development of new TRPM8 antagonists suitable for the topical treatment of ocular painful conditions and identified two new compounds (51 and 59), N-alkoxy amide derivatives, that can permeate across ocular tissue and reduce the behavioral responses induced by the topical ocular menthol challenge in vivo.

瞬时受体电位褪黑素8（Transient receptor potential melastatin 8, TRPM8）在疼痛调控与感知过程中发挥关键作用，TRPM8拮抗剂已被提出作为疼痛治疗的潜在治疗策略。此前，本团队开发了两款TRPM8拮抗剂，并将其作为局部与全身性疼痛治疗的候选药物。本文详述了这两款TRPM8拮抗剂（编号27与45）的设计与合成流程，以及对生物电子等排化学基团进行调控与替换的理性设计思路，借此确定了pKa与LogD值的窄范围组合，该组合是最终优化其效价强度与代谢稳定性的核心要素。基于相同的研发思路，本团队进一步开发了适用于眼部疼痛病症局部治疗的新型TRPM8拮抗剂，并筛选得到两款N-烷氧基酰胺类衍生物（编号51与59），它们可穿透眼部组织，并在体内有效降低局部眼部薄荷醇刺激诱导的行为学反应。