Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
Lilly Biotechnology Center, Eli Lilly and Company, San Diego, California 92121, United States.
J Med Chem. 2021 May 13;64(9):5470-5484. doi: 10.1021/acs.jmedchem.0c01918. Epub 2021 Apr 14.
The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy . Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound , which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.
Th17 通路与自身免疫性疾病有关。维甲酸受体相关孤儿受体 C2（RORγt）是 Th17 细胞的主要调节因子，控制着 IL-17A 的表达。RORγt 主要在产生 IL-17A 的淋巴样细胞中表达。在这里，我们描述了配体结合口袋的虚拟筛选，以及随后在结合测定中的筛选，该筛选确定了 1-苄基-4'，5'-二氢螺[哌啶-4,7'-噻吩[2,3-]吡喃]-2'-甲酰胺支架作为基于结构设计指导的结合亲和力和功能活性优化的起点。化合物在小鼠 PK/PD 模型中具有活性，并在炎症性关节炎小鼠模型中具有疗效，这些模型用于定义疗效所需的靶标结合的水平和持续时间。进一步的优化旨在改善 ADME 和物理化学性质，并在模拟和建模的指导下提供化合物，预计该化合物将在临床上达到疗效所需的靶标结合的水平和持续时间。
