38504-24-4Relevant academic research and scientific papers
Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues
Downs, Ryan P.,Xiao, Zhousheng,Ikedionwu, Munachi O.,Cleveland, Jacob W.,Lin Chin, Ai,Cafferty, Abigail E.,Darryl Quarles,Carrick, Jesse D.
, (2021)
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.
FIBROBLAST GROWTH FACTOR 23 ANTAGONISTS AND RELATED COMPOSITIONS AND METHODS
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Page/Page column 25-26, (2019/05/15)
This disclosure relates to small molecule inhibitors of Fibroblast growth factor 23 (FGF-23) and related compositions and methods of treatment.
