Martucci Cataldo, Allen Andrew Dennis, Moretto Nadia, Bagnacani Valentina, Fioni Alessandro, Patacchini Riccardo, Civelli Maurizio, Villetti Gino, Facchinetti Fabrizio
Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
Front Pharmacol. 2024 Mar 14;15:1343941. doi: 10.3389/fphar.2024.1343941. eCollection 2024.
Inhibition of p38 mitogen-activated protein kinase (MAPKs) is a potential therapeutic approach for the treatment of acute and chronic pulmonary inflammatory conditions. Here, we report the and characterization of the anti-inflammatory effects of CHF6297, a novel potent and selective p38α inhibitor designed for inhalation delivery as a dry powder formulation. CHF6297 has been proven to inhibit p38α enzymatic activity with sub-nanomolar potency (IC = 0.14 ± 0.06 nM), with >1,000-fold selectivity against p38γ and p38δ. In human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides (LPS), as well as in human bronchial epithelial cells (BEAS2B) stimulated with TNF-α or cigarette smoke extract (CSE), CHF6297 inhibited interleukin (IL)-8 release with low nanomolar potency. CHF6297 administered to rats by using a nose-only inhalation device as a micronized dry powder formulation blended with lactose dose-dependently inhibited the LPS-induced neutrophil influx in the bronchoalveolar lavage fluid (BALF). CHF6297 administered intratracheally to rats dose-dependently counteracted the IL-1β (0.3 mg/kg)-induced neutrophil influx (ED = 0.22 mg/kg) and increase in IL-6 levels (ED = 0.82 mg/kg) in the BALF. In mice exposed to tobacco smoke (TS), CHF6297, administered intranasally (i.n.) for 4 days at 0.03 or 0.3 mg/kg, dose-dependently inhibited the corticosteroid-resistant TS-induced neutrophil influx in the BALF. In a murine house dust mite (HDM) model of asthma exacerbated by influenza virus A (IAV) (H3N3), CHF6297 (0.1 mg/kg, i.n.) significantly decreased airway neutrophilia compared to vehicle-treated IAV/HDM-challenged mice. When CHF6297, at a dose ineffective (0.03 mg/kg), was added to budesonide, it augmented the anti-inflammatory effects of the steroid. Overall, CHF6297 effectively counteracted lung inflammation in experimental models where corticosteroids exhibit limited anti-inflammatory activity, suggesting a potential for the treatment of acute exacerbations associated with chronic obstructive pulmonary disease (COPD) and asthma, acute lung injury (ALI), and viral-induced hyperinflammation.
抑制p38丝裂原活化蛋白激酶（MAPKs）是治疗急慢性肺部炎症性疾病的一种潜在治疗方法。在此，我们报告了CHF6297的抗炎作用的 和 特征，CHF6297是一种新型强效且选择性的p38α抑制剂，设计为干粉制剂用于吸入给药。已证明CHF6297以亚纳摩尔效力（IC = 0.14±0.06 nM）抑制p38α酶活性，对p38γ和p38δ的选择性大于1000倍。在用脂多糖（LPS）刺激的人外周血单核细胞（PBMCs）以及用TNF-α或香烟烟雾提取物（CSE）刺激的人支气管上皮细胞（BEAS2B）中，CHF6297以低纳摩尔效力抑制白细胞介素（IL）-8释放。通过使用仅鼻吸入装置将CHF6297作为与乳糖混合的微粉化干粉制剂给予大鼠，剂量依赖性地抑制支气管肺泡灌洗液（BALF）中LPS诱导的中性粒细胞流入。经气管内给予大鼠CHF6297剂量依赖性地抵消了IL-1β（0.3 mg/kg）诱导的中性粒细胞流入（ED = 0.22 mg/kg）以及BALF中IL-6水平的升高（ED = 0.82 mg/kg）。在暴露于烟草烟雾（TS）的小鼠中，以0.03或0.3 mg/kg鼻内（i.n.）给予CHF6297 4天，剂量依赖性地抑制了BALF中对皮质类固醇耐药的TS诱导的中性粒细胞流入。在甲型流感病毒（IAV）（H3N3）加剧的小鼠屋尘螨（HDM）哮喘模型中，与载体处理的IAV/HDM攻击小鼠相比，CHF6297（0.1 mg/kg，i.n.）显著降低了气道中性粒细胞增多。当以无效剂量（0.03 mg/kg）的CHF6297添加到布地奈德中时，它增强了类固醇的抗炎作用。总体而言，CHF6297在皮质类固醇抗炎活性有限的实验模型中有效抵消了肺部炎症，表明其在治疗与慢性阻塞性肺疾病（COPD）和哮喘、急性肺损伤（ALI）以及病毒诱导的过度炎症相关的急性加重方面具有潜力。
