80622-23-7Relevant academic research and scientific papers
Design and Structural Optimization of Dual FXR/PPARδActivators
Schierle, Simone,Neumann, Sebastian,Heitel, Pascal,Willems, Sabine,Kaiser, Astrid,Pollinger, Julius,Merk, Daniel
supporting information, p. 8369 - 8379 (2020/08/12)
Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δhave been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPAR?-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδactivator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδand was structurally refined to a potent and balanced FXR/PPARδactivator in a computer-aided fashion. The resulting dual FXR/PPARδmodulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.
A convenient method for the preparation of 4-aryloxyphenols
Yeager,Schissel
, p. 63 - 68 (2007/10/02)
A convenient method for the preparation of 4-aryloxyphenols via the homologation of preformed phenols is described. Condensation of various 4-substituted phenols with either 4-fluorobenzaldehyde (8) or 4-fluoroacetophenone (9) yielded the corresponding 4-aryl-oxybenzaldehydes, 10, and acetophenones, 11, in 70-93% yield. Baeyer-Villiger oxidation of these materials with 3-chloroperoxybenzoic acid (MCPBA) yielded the corresponding 4-formyloxy and 4-acetoxyphenyl ethers which were hydrolyzed without purification to the desired 4-aryloxyphenols 12 in 72-94% yield. Both 4-fluorobenzaldehyde (8) and 4-fluoroacetophenone (9) are synthetically equivalent to the a4 umpoled synthon 6. Extension of this methodology of the preparation of 4,4'-[arylbis(oxy)]bisphenols from aromatic diols is also described. Condensation of various aromatic diols with 8 or 9 yielded the corresponding 4,4'-[arylbis(oxy)]bisbenzaldehydes 15 and acetophenones 16 in 71-89% yield. Baeyer-Villiger oxidation of these compounds with MCPBA yielded the desired 4,4'-[arylbis(oxy)]bisphenyl bisformates 17 and bisacetates 18 in 67-84% yield. Hydrolysis of these compounds afforded the desired 4,4'-[arylbis(oxy)bisphenols 19 in 70-91% yield.
