86793-93-3

Upstream product

• 1123-56-4 2,6-dimethylbenzaldehyde 
• 15855-34-2 N-[(2,6-dimethylphenyl)methylidene]hydroxylamine 

Downstream Products

• 87828-91-9 3-(2,6-Dimethylphenyl)-1,2-benzisoxazole 
• 1374961-74-6 (3-(2,6-dimethylphenyl)-5-isopropylisoxazol-4-yl)methanol 
• 1374961-76-8 C₁₅H₁₈BrNO 
• 1374961-79-1 2-chloro-4-{[3-(2,6-dimethylphenyl)-5-isopropylisoxazol-4-yl]methoxy}benzaldehyde 
• 1374961-82-6 2-chloro-4-{[3-(2,6-dimethylphenyl)-5-isopropylisoxazol-4-yl]methoxy}benzoic acid 
• 1374961-85-9 methyl 3-{N-benzyl-2-chloro-4-{[3-(2,6-dimethylphenyl)-5-isopropylisoxazol-4-yl]methoxy}benzamido}benzoate 
• 1374961-94-0 3-(N-benzyl-2-chloro-4-((3-(2,6-dimethylphenyl)-5-isopropylisoxazol-4-yl)methoxy)benzamido)benzoic acid 
• 1374961-73-5 methyl 3-(2,6-dimethylphenyl)-5-isopropylisoxazole-4-carboxylate 
• 1315451-30-9 [3-(2, 6-dimethyl-phenyl)-5-methyl-isoxazol-4-yl]-methanol 
• 1104461-64-4 3-(2,6-dimethyl-phenyl)-5-methyl-isoxazole-4-carboxylic acid methyl ester 

Relevant academic research and scientific papers

Design and Structural Optimization of Dual FXR/PPARδActivators

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.

HORMONE RECEPTOR MODULATORS FOR TREATING METABOLIC CONDITIONS AND DISORDERS

The invention relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): (I), wherein L1, A, X1, X2, R1, R2, and R3 are described herein.

Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism

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.

Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by hereditary mutations of bile salt export pump (BSEP), such as E297G BSEP, which is a folding-defective mutant that is unable to traffic beyond the endoplasmic reticulum (ER). 4-Phen