Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5.
Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.
结核病是造成全球范围内死亡率和经济负担的主要原因，尤其是在中低收入国家。鉴于临床环境中耐多药结核分枝杆菌菌株的显著且持续增加，迫切需要开发新的、安全有效的治疗方法。本文描述了一种基于融合二氢吡咯并嘧啶骨架的类药系列化合物的开发。该系列化合物是针对结核分枝杆菌赖氨酸-tRNA 合成酶（LysRS）开发的，细胞研究支持这种作用机制。先导化合物 DDD02049209 在急性和慢性结核的小鼠模型中具有疗效，并且具有合适的理化、药代动力学特性和体外安全性特征，支持进一步开发。重要的是，使用临床耐药株进行的初步分析表明，该骨架不存在针对该结构的临床耐药性。
