495417-33-9Relevant academic research and scientific papers
Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
, p. 1184 - 1199 (2015/07/07)
Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
Highly substituted isoxazoles: The Baylis-Hillman reaction of substituted 4-isoxazolecarbaldehydes and attempted cyclization to isoxazole-annulated derivatives
Roy, Amrendra K.,Batra, Sanjay
, p. 1347 - 1356 (2007/10/03)
In an attempt to understand the effect of position of the formyl group on the efficiency of Baylis-Hillman reaction within isoxazolecarbaldehydes, the reactions of substituted 4-isoxazolecarbaldehydes to obtain highly substituted isoxazoles are described. Attempts to obtain isoxazole-annulated derivatives from these Baylis-Hillman adducts involving SNR′-SNAr substitution strategy are also described.
Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines
Zamponi, Gerald W.,Stotz, Stephanie C.,Staples, Richard J.,Andro, Tina M.,Nelson, Jared K.,Hulubei, Victoria,Blumenfeld, Alex,Natale, Nicholas R.
, p. 87 - 96 (2007/10/03)
A series of 4-isoxazolyl-1,4-dihydropyridines (IDs) were prepared and characterized, and their interaction with the calcium channel was studied by patch clamp analysis. The structureactivity relationship (SAR) that emerges is distinct from the 4-aryldihydropyridines (DHPs), and affinity increases dramatically at higher holding potentials. Thus, among the 3′-arylisoxazolyl analogues p-Br > p-Cl ? p-F, and p-Cl > m-Cl > o-Cl ? o-MeO. Four of the analogues were examined by single-crystal X-ray diffractometry, and all were found to adopt an O-exo conformation in the solid state. The calculated barrier to rotation, however, suggests that rotation about the juncture between the heterocyclic rings is plausible under physiological conditions. A variable-temperature NMR study confirmed the computation. With Striessnig's computational sequence homologation procedure, a working hypothesis was derived from the data that explains the unique SAR for IDs.
