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Discovery of Novel TRPM8 Blockers Suitable for the Treatment of Somatic and Ocular Painful Conditions: A Journey through pKa and LogD Modulation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jmedchem.1c01647 Gianluca Bianchini 1 , Mara Tomassetti 2 , Samuele Lillini 2 , Anna Sirico 2 , Silvia Bovolenta 3 , Lorena Za 3 , Chiara Liberati 3 , Rubina Novelli 4 , Andrea Aramini 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jmedchem.1c01647 Gianluca Bianchini 1 , Mara Tomassetti 2 , Samuele Lillini 2 , Anna Sirico 2 , Silvia Bovolenta 3 , Lorena Za 3 , Chiara Liberati 3 , Rubina Novelli 4 , Andrea Aramini 1
Affiliation
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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.
中文翻译：
发现适用于治疗躯体和眼部疼痛的新型 TRPM8 阻滞剂：pKa 和 LogD 调制之旅
瞬时受体电位 melastatin 8 (TRPM8) 与疼痛调节和感知至关重要，TRPM8 拮抗剂已被提议作为疼痛治疗的潜在治疗方法。此前，我们开发了两种 TRPM8 拮抗剂，并提出将它们作为局部和全身疼痛治疗的候选药物。在这里，我们描述了这两种 TRPM8 拮抗剂（27和45）的设计和合成，以及调节/替换生物等排化学基团的合理方法，这使我们能够确定窄范围 p K a的组合和 LogD 值，这对于最终优化其效力和代谢稳定性至关重要。按照同样的方法，我们随后开发了适用于局部治疗眼部疼痛的新型 TRPM8 拮抗剂，并确定了两种新化合物（51和59），即N-烷氧基酰胺衍生物，它们可以渗透到眼部组织并减少行为体内局部眼部薄荷醇激发诱导的反应。
更新日期：2021-11-25
中文翻译：
发现适用于治疗躯体和眼部疼痛的新型 TRPM8 阻滞剂：pKa 和 LogD 调制之旅
瞬时受体电位 melastatin 8 (TRPM8) 与疼痛调节和感知至关重要，TRPM8 拮抗剂已被提议作为疼痛治疗的潜在治疗方法。此前，我们开发了两种 TRPM8 拮抗剂，并提出将它们作为局部和全身疼痛治疗的候选药物。在这里，我们描述了这两种 TRPM8 拮抗剂（27和45）的设计和合成，以及调节/替换生物等排化学基团的合理方法，这使我们能够确定窄范围 p K a的组合和 LogD 值，这对于最终优化其效力和代谢稳定性至关重要。按照同样的方法，我们随后开发了适用于局部治疗眼部疼痛的新型 TRPM8 拮抗剂，并确定了两种新化合物（51和59），即N-烷氧基酰胺衍生物，它们可以渗透到眼部组织并减少行为体内局部眼部薄荷醇激发诱导的反应。
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