20637-08-5Relevant articles and documents
Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease
Yu, Donna D.,Van Citters, Gregg,Li, Hongzhi,Stoltz, Brian M.,Forman, Barry M.
, (2021)
Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPARα (peroxisome proliferator-activated receptor α) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPARα agonists as potential therapies for NAFLD. However, how PPARα coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPARα modulators activate PPARα by up-regulating PPARα target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPARα agonists are described.
An Iron-Mesoionic Carbene Complex for Catalytic Intramolecular C-H Amination Utilizing Organic Azides
Albrecht, Martin,Keilwerth, Martin,Meyer, Karsten,Pividori, Daniel M.,Stroek, Wowa
supporting information, p. 20157 - 20165 (2021/12/09)
The synthesis of N-heterocycles is of paramount importance for the pharmaceutical industry. They are often synthesized through atom economic and environmentally unfriendly methods, generating significant waste. A less explored, but greener, alternative is
Efficient C-H Amination Catalysis Using Nickel-Dipyrrin Complexes
Betley, Theodore A.,Clarke, Ryan M.,Dong, Yuyang,Porter, Gerard J.
supporting information, p. 10996 - 11005 (2020/07/08)
A dipyrrin-supported nickel catalyst (AdFL)Ni(py) (AdFL: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile. A large, primary intermolecular kinetic isotope effect (KIE = 31.9 ± 1.0) suggests H-atom abstraction (HAA) is the rate-determining step, indicative of H-atom tunneling being operative. The reaction rate has first order dependence in the catalyst and zeroth order in substrate, consistent with the resting state of the catalyst as the corresponding nickel iminyl radical. The presence of the nickel iminyl was determined by multinuclear NMR spectroscopy observed during catalysis. The activation parameters (ΔH? = 13.4 ± 0.5 kcal/mol; ΔS?= -24.3 ± 1.7 cal/mol·K) were measured using Eyring analysis, implying a highly ordered transition state during the HAA step. The proposed mechanism of rapid iminyl formation, rate-determining HAA, and subsequent radical recombination was corroborated by intramolecular isotope labeling experiments and theoretical calculations.