Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases

Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.磷酸二酯酶4（Phosphodiesterase 4, PDE4）是参与炎症性疾病发病进程的关键环磷酸腺苷（cAMP）代谢酶，其药理学抑制作用已被证实可在慢性阻塞性肺疾病（COPD）中发挥治疗功效。本研究报道了一项药物发现项目，旨在筛选适用于肺部给药的新型强效PDE4抑制剂类别。研究团队从前期开发的苯甲酸酯类化合物系列出发，对该酶催化结合口袋的溶剂暴露区域展开化学空间探索。通过大规模结构修饰，最终发现了多款杂环烷基酯类强效体外PDE4抑制剂。其中，(S*,S**)-18e与(S*,S**)-22e展现出最优的体外ADME（吸收、分布、代谢、排泄）及药代动力学特性，并在实验动物模型中呈剂量依赖性地缓解急性肺嗜酸性粒细胞增多症。该类化合物兼具优异的生物学活性与固态理化性质，提示二者均具备成为治疗呼吸炎症性疾病的有效局部给药制剂的潜力。