Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore.
Eur J Med Chem. 2020 Oct 15;204:112481. doi: 10.1016/j.ejmech.2020.112481. Epub 2020 Jul 12.
Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions. The cell-based SAR studies permitted the assessment of the inhibitor efficacy in more complex systems, which were often limited in traditional covalent drug development using isolated proteins or peptides. Our in vitro study identified enone 17 as the most promising candidate which demonstrated potent anti-inflammatory activity and superior safety profiles as compared to the lead compound andrographolide. Its reversibility following a Michael addition reaction with biological thiols resulted in more predictable pharmacological responses. In addition, 17 exhibited good in vivo efficacy at doses as low as 0.3 mg/kg when tested in LPS-induced acute lung injury model. Given a good balance of chemical reactivity and biological potency, enone 17 potentially offers a new therapeutic option based on natural product chemistry for the management of inflammatory conditions.
具有长效作用的共价药物通常显示出更高的效力，然而，缺乏优化其结构和电子特征的综合策略。在此，我们致力于了解化学反应性对生物效力的贡献，以便基于 ent-ladane 穿心莲内酯支架为抗炎作用合理设计新的共价抑制剂。具体而言，开发了一系列包含各种迈克尔受体的穿心莲内酯衍生物，并在各种化学和生物学条件下测定了它们的巯基反应性。基于细胞的 SAR 研究允许在更复杂的系统中评估抑制剂的功效，而这些系统在使用分离的蛋白质或肽的传统共价药物开发中往往受到限制。我们的体外研究确定烯酮 17 是最有前途的候选物，与先导化合物穿心莲内酯相比，它表现出强大的抗炎活性和更好的安全性。与生物硫醇发生迈克尔加成反应后，其可逆性导致更可预测的药理反应。此外，在 LPS 诱导的急性肺损伤模型中，当以 0.3mg/kg 的低剂量测试时，17 表现出良好的体内功效。鉴于化学反应性和生物效力之间的良好平衡，烯酮 17 可能为基于天然产物化学的炎症疾病管理提供新的治疗选择。
