Design of potent PPARα agonists

Pharmacophore Identification for Peroxisome Proliferator-Activated Receptor Gamma Agonists

“…The structure and biological activity data for 2110 PPAR agonists were col- lected from the published journals. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Finally, 1080 compounds were selected for the PPARγ agonist database after filtering process. The next step is the selection of training set and the following five general guidelines were applied for the selection.…”

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

“…Modeling experiments were performed to predict the binding mode of this part of the ligand; the results suggest that part of the receptor subtype profile could be due to interactions with amino acid residues in the lipophilic pocket close to the receptor surface. Surprisingly, the dimeric ligand (51) exhibited excellent pharmacokinetic properties despite breaking all the "rule of five" criteria [77,79]. A further modification of compound (49) was achieved by removing the olefine methyl and the para-phenyl ring and introducing substituents in meta-positions of the resulting compound.…”

“…Some potent and selective PPAR agonists were obtained with substituents having van der Waals volume around 260. Compound (52) displayed the highest PPAR selectivity with a potency ratio to PPAR and PPAR of 410 and 2000, respectively [79]. Fig.…”

Formal Synthesis of Actinoranone Using a Racemization-Free One-Pot Semipinacol Rearrangement/Wittig Reaction

“…The required silylated epoxyalcohol was prepared starting from the readily available allylic alcohol 12 (Scheme 3). 42 A catalytic Sharpless epoxidation 43 followed by treatment with TBSOTf permitted stereoselective preparation of the epoxy silyl ether required for the rearrangement in good yield and excellent enantiomeric excess (10, Scheme 3). At this point, we investigated the antiperiplanar migration of the vicinal C-C bond to benzylic position using a Yamamoto rearrangement.…”

“…The crude product was purified by column chromatography (npentane) yielding vinyl iodide 2 (44.0 mg, 0.154 mmol, 94%) as colorless solid. (12) 42,54 Triethyl phosphonoacetate (6.05 mL, 14.1 mmol, 1.8 equiv) was added to a suspension of NaH (60 w% mineral oil; 0.580 g, 24.0 mmol, 1.8 equiv) in anhydrous THF (71 mL) at 0 °C. The suspension cleared after stirring for 30 min, and then a solution of the 3,5-dimethoxybenzaldehyde (7, 2.00 g, 12.0 mmol, 1.0 equiv) in anhydrous THF (4.0 mL) was added.…”