Zhang Hongjun, Lapointe Blair T, Anthony Neville, Azevedo Rita, Cals Jos, Correll Craig C, Daniels Matthew, Deshmukh Sujal, van Eenenaam Hans, Ferguson Heidi, Hegde Laxminarayan G, Karstens Willem Jan, Maclean John, Miller J Richard, Moy Lily Y, Simov Vladimir, Nagpal Sunil, Oubrie Arthur, Palte Rachel L, Parthasarathy Gopal, Sciammetta Nunzio, van der Stelt Mario, Woodhouse Janice D, Trotter B Wesley, Barr Kenneth
Medicinal Chemistry, Discovery Biology, Discovery Process Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Discovery Pharmaceutical Sciences, Modeling & Informatics, In Vitro and In Vivo Pharmacology, and Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Medicinal Chemistry, Discovery Biology, and Computational and Structural Chemistry, Merck Sharp & Dohme, Molenstraat 110, Oss 5342 CC, The Netherlands.
ACS Med Chem Lett. 2020 Jan 9;11(2):114-119. doi: 10.1021/acsmedchemlett.9b00431. eCollection 2020 Feb 13.
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit , a tool compound was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of , which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.
抗白细胞介素-17单克隆抗体（即可善挺和拓咨）的临床成功验证了通过调节Th17通路来治疗自身免疫性疾病的可行性。核激素受体RORγt是Th17细胞的主要调节因子，可影响包括白细胞介素-17A、白细胞介素-17F、白细胞介素-22、白细胞介素-26和粒细胞-巨噬细胞集落刺激因子在内的多种细胞因子的产生。学术界和工业界都对寻找适合抑制RORγt的小分子产生了浓厚兴趣。在过去几年中已报道了多种RORγt抑制剂，其中大多数是正构结合剂。在此，我们披露了一类与别构结合口袋以不同方式结合的抑制剂的发现和优化过程。从一个活性较弱的先导化合物开始，很快鉴定出一种工具化合物，它表现出卓越的效力、选择性和脱靶特性。进一步的优化集中在提高代谢稳定性上。用哌啶基羧酸酯取代苯甲酸部分，将中的4-氮杂吲唑核心修饰为4-氟吲唑，并引入一个关键的羟基，从而发现了，它具有出色的效力和选择性，以及适合口服给药的改善的药代动力学特征。
