Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiation

Physiological Functions of Peroxisome Proliferator-Activated Receptor β

“…EC 50 values for these compounds when assessed with human recombinant PPAR␤ are ϳ1 nM for GW501516 and GW0742, 2 nM for MBX-8025, and 50 nM for L-165041, with 250-to 1,000-fold selectivity over the human PPAR␣ and PPAR␥ isoforms (41, 43, 311) (FIGURE 2). Other specific and potent PPAR␤ synthetic agonists (350,494) and antagonists (200,530) have been described more recently, and all these compounds have been very useful tools for elucidating the bio- logical roles of PPAR␤. Although PPAR␤ agonists are not yet in clinical use, human studies have been performed to test the efficacy of two compounds, GW501516 and MBX-8025, providing very encouraging findings for the treatment of metabolic disorders in dyslipidemic obese individuals.…”

Biological evaluation of novel benzisoxazole derivatives as PPARδ agonists

“…The outline of the synthesis method for an oxazole derivative, compound 6, has been reported previously. 15 A similar method was used for synthesizing compounds 3, 4, and 7-17. Thiazole derivatives, compounds 5 and 18, by using the method given below.…”

“…The crystals were filtered, washed with water, air-dried overnight, and further dried in vacuo to give the target compound as a white powder (7.90 g, yield 94%). The titled compound was synthesized from 6-acetamido-3,5-dimethyl-1,2-benzisoxazole (23a) 15 and incubated for 5 min at room temperature. Fifty microliters of reaction stopping solution (1 M sodium carbonate solution) was added.…”

“…and 4-chloromethyl-2-(2, -dichlorophenyl)-5-isopropyloxazole (28)15 in the same manner as that described for 24:1 H NMR (CDCl 3 , 400 MHz) d: 1.10 (6H, d, J = 7 Hz), 2.24 (3H, br s), 2.26(3H, s), 2.92 (1H, m), 3.05 (2H, t, J = 7 Hz), 3.33 (2H, t, J = 7 Hz), 7.16 (1H, br s), 7.28 (1H, s), 7.32 (1H, dd, 1H, J = 2 Hz, 9 Hz), 7.51 (1H, d, J = 2 Hz), 7.91 (1H, d, 1 J = 9 Hz), 8.34 (1H, br s).5.1.11. 6-Amino-3-[2-[2-(2,4-dichlorophenyl)-4-isopropyl-4-oxazolyl]ethyl]-5-methyl-1,2-benzisoxazole (30)The titled compound was synthesized in the same manner as that described for 25:1 H NMR (CDCl 3 , 400 MHz) d: 1.10 (6H, d, J = 7 Hz), 2.14 (3H, s), 2.92 (1H, m), 3.03 (2H, t, J = 7 Hz), 3.27 (2H, t, J = 7 Hz), 3.97 (2H, br s), 6.72 (1H, s), 7.13 (1H, s), 7.32 (1H, dd, J = 2 Hz, 8 Hz), 7.51 (1H, d, J = 2 Hz), 7.92 (1H, d, 1 J = 8 Hz), 8.34 (1H, br s).…”

Nuclear Receptor Modulators — Current Approaches and Future Perspectives

“…So far, a large bunch of receptor agonists have been identified that advanced research on this PPAR subtype and its physiological role [48]. Recently, a benzisoxazole has been identified as PPARδ-selective agonist with an EC 50 -value of 4.5 nM as determined using a cell-based assay [49]. Another example is GW501516, a PPARδ ligand developed by GlaxoSmithKline that has been identified by combinatorial chemistry and structure-based design [50].…”