Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area. Current outcomes described in this work highlight efforts related to lead identification and modification using organic synthesis of strategic analogues to probe structure-activity relationships and preliminarily define the pharmacophore of a computationally derived hit obtained from virtual high-throughput screening. Synthetic strategies for the initial hit and analogue preparation, as well as preliminary cellular in vitro assay results highlighting sub micromolar inhibition of the FGF-23 signaling sequence at a concentration well below cytotoxicity are reported herein.

遗传性低磷血症、TIO 和 CKD 病症被认为受到过量成纤维细胞生长因子 - 23 (FGF-23) 的影响，FGF-23 会激活二元肾 FGFR / α-Klotho 复合物来调节磷酸盐和维生素 D 的稳态代谢。具有过量 FGF-23 的 CKD 患者的 FGF-23 反应常常导致心血管疾病死亡率增加。该领域的研究和开发尚未出现可逆结合的小分子治疗剂。这项工作中描述的当前结果强调了与使用战略类似物的有机合成来探测结构-活性关系的先导化合物识别和修饰相关的工作，并初步定义了从虚拟高通量筛选中获得的计算衍生命中的药效团。本文报道了初始命中和类似物制备的合成策略，以及初步细胞体外测定结果，强调了在远低于细胞毒性的浓度下对 FGF-23 信号序列的亚微摩尔抑制。