Chemistry Research and Drug Design, ∥Pharmacology and Toxicology, ‡Pharmacokinetics Biochemistry and Metabolism, †Analytics and Early Formulations, #Project Leader Corporate Drug Development, and ⊥Corporate Pre-Clinical R&D Director, Chiesi Farmaceutici S.p.A , Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
J Med Chem. 2017 Dec 28;60(24):10026-10046. doi: 10.1021/acs.jmedchem.7b01044. Epub 2017 Dec 14.
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（PDE4）是一种关键的 cAMP 代谢酶，参与炎症性疾病的发病机制，其药理学抑制已被证明在慢性阻塞性肺疾病（COPD）中具有治疗效果。在此，我们描述了一个旨在发现新型强效 PDE4 抑制剂的药物发现计划，这些抑制剂适合肺部给药。从以前的一系列苯甲酸酯开始，我们探索了酶催化结合口袋溶剂暴露区域的化学空间。广泛的结构修饰导致发现了许多杂环烷基酯作为强效的体外 PDE4 抑制剂。特别是（S*，S**）-18e 和（S*，S**）-22e，表现出最佳的体外 ADME 和药代动力学特性，并在实验动物模型中剂量依赖性地对抗急性肺嗜酸性粒细胞增多症。最佳的生物学特征以及出色的固态特性表明，这两种化合物都有可能成为治疗呼吸道炎症性疾病的有效局部药物。
