38504-23-3Relevant 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.
, (2020/11/30)
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
-
Page/Page column 25-26; 29, (2019/05/15)
This disclosure relates to small molecule inhibitors of Fibroblast growth factor 23 (FGF-23) and related compositions and methods of treatment.
A STUDY OF PERISELECTIVITY IN THE THERMAL CYCLISATION REACTIONS OF DIENE-CONJUGATED DIAZO COMPOUNDS: 1,7-CYCLISATION AS A ROUTE TO 3H-1,2-DIAZEPINES AND 1,5-CYCLISATION LEADING TO NEW REARRANGEMENT REACTIONS OF 3H-PYRAZOLES
Robertson, Ian R.,Sharp, John T.
, p. 3095 - 3112 (2007/10/02)
A range of diene-conjugated diazo compounds has been generated by the thermal decomposition of the sodium salts of the tosylhydrazones of 1-acyl-1,3-dienes. Those of type (21) with a cis relationship of the diazo group and the γ,δ-double bond and having a cis hydrogen atom at the dien terminus cyclised only by 1,7 ring closure to give 3H-1,2-diazepines (23).This mode of cyclisation was inhibited by the presence of cis methyl or phenyl groups at the diene terminus eg in (45). Compounds of this type cyclised by the alternative 1,5- ring closure to give 3-alkenyl-3H-pyrazoles eg (46) as primary products. These observations are explained on the basis of a helical transition state (54) for the 8? electron 1,7-electrocyclisation reaction. Diene-conjugated diazo compounds with a trans γ,δ double bond eg (32) also cyclised predominantly by 1,5-electrocyclisation to give 3-alkenyl-3H-pyrazoles eg (33). In most cases the 3H-pyrazoles rearranged under the reaction conditions via alkenyl group and hydrogen migrations to give 1H-pyrazoles eg (34) and (37).
