Bhattacharjee Abir, Sinha Antara, Ratia Kiira, Yin Liang, Delgado-Rivera Loruhama, Petukhov Pavel A, Thatcher Gregory R J, Wardrop Duncan J
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States.
Department of Medicinal Chemistry & Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
ACS Med Chem Lett. 2017 Nov 21;8(12):1241-1245. doi: 10.1021/acsmedchemlett.7b00313. eCollection 2017 Dec 14.
Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS.
硫化氢由L-半胱氨酸通过胱硫醚γ-裂解酶（CSE）和胱硫醚β-合酶（CBS）的作用产生，并且越来越多地发现在一系列生理过程中发挥着深远的调节作用。越来越多的证据表明，在包括类风湿性关节炎、高血压、缺血性损伤和睡眠呼吸紊乱在内的几种疾病状态下，硫化氢生物合成会上调。除了作为我们理解硫化氢生物学的关键工具外，CSE抑制剂对于治疗这种气体信号分子水平升高起作用的疾病具有治疗潜力。我们描述了一系列新型强效CSE抑制剂的发现和开发，这些抑制剂比基准抑制剂表现出更高的活性，并且重要的是，对CSE相对于CBS具有高选择性。
