Wei Jun, Gu Dongyan, Yuan Leer, Sheng Rong
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China.
Curr Med Chem. 2023;30(17):1971-1992. doi: 10.2174/0929867329666220819115011.
Bronchial asthma is the most common chronic respiratory illness, the incidence of which continues to increase annually. Currently, effective treatments for CS-resistant asthma and severe asthma are still lacking, and new therapeutic regimens are urgently required. PI3Kδ is a key enzyme in hematopoietic cells and represents a major target for oncology and inflammatory disease (particularly respiratory disease, asthma and COPD). In the case of respiratory disease, the ability to inhibit PI3Kδ in the lungs shows a higher safety and therapeutic index relative to systemic inhibition. In recent years, paradigm shifts have occurred in inhalation therapeutics for systemic and topical drug delivery due to the favorable properties of lungs, including their large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including a non-invasive route of administration, low metabolic activity, a controlled environment for systemic absorption and the ability to avoid first bypassing metabolism. In this review, we focus on the discovery and development of inhaled drugs targeting PI3Kδ for asthma by focusing on their activity and selectivity, in addition to their potential in drug design strategies using inhaled administration.
支气管哮喘是最常见的慢性呼吸道疾病，其发病率每年持续上升。目前，针对糖皮质激素抵抗性哮喘和重度哮喘仍缺乏有效的治疗方法，迫切需要新的治疗方案。PI3Kδ是造血细胞中的关键酶，是肿瘤学和炎症性疾病（特别是呼吸系统疾病、哮喘和慢性阻塞性肺疾病）的主要靶点。在呼吸系统疾病方面，相对于全身抑制，在肺部抑制PI3Kδ的能力具有更高的安全性和治疗指数。近年来，由于肺部具有大表面积和高渗透性等有利特性，全身和局部给药的吸入疗法发生了范式转变。肺部给药具有许多优点，包括非侵入性给药途径、低代谢活性、全身吸收的可控环境以及避免首过代谢的能力。在本综述中，我们除了关注吸入给药在药物设计策略中的潜力外，还将重点关注靶向PI3Kδ的吸入药物用于哮喘的发现和开发，重点关注其活性和选择性。
