A novel class of PPARγ ligand 1 (EC 50 = 197 nM) with a dibenzoazepin scaffold was identified through highthroughput screening campaign. To avoid the synthetically troublesome chiral center of 1, its conformational analysis using the MacroModel was conducted, focusing on conformational flip of the tricyclic ring and the conformational restriction by the methyl group at the chiral center. On the basis of this analysis, scaffold hopping of dibenzoazepine into dibenzo[b,e]oxepine by replacing the chiral structures with the corresponding olefinic E/Z isomers was performed. Consequently, dibenzo[b,e]oxepine scaffold 9 was developed showing extremely potent PPARγ reporter activity (EC 50 = 2.4 nM, efficacy = 9.5%) as well as differentiation-inducing activity against a gastric cancer cell line MKN-45 that was more potent than any other well-known PPARγ agonists in vitro (94% at 30 nM). The X-ray crystal structure analysis of 9 complexed with PPARγ showed that it had a unique binding mode to PPARγ ligand-binding domain that differed from that of any other PPARγ agonists identified thus far.

A functionalized spiro[4.5]decane framework was synthesized by the Claisen rearrangement of 4-substituted bicyclic dihydropyrans in a highly stereoselective fashion.

Cyclohexane derivatives Q 0040 Stereoselective Synthesis of Functionalized Spiro[4.5]decanes by Claisen Rearrangement of Bicyclic Dihydropyrans. -The Claisen rearrangement of various 4-substituted bicyclic dihydropyrans, e.g. (VI), (VIII), (X), and (XII) affords functionalized spiro[4.5]decanes (VII), (IX), (XI) and (XIII) in a highly stereoselective manner and with moderate to good yields. Some further transformations of the obtained spiro-decane (XIII) are also included. -(NAKAZAKI, A.; MIYAMOTO, H.; HENMI, K.; KOBAYASHI*, S.; Synlett 2005, 9, 1417-1420; Fac. Pharm. Sci., Sci. Univ. Tokyo, Noda, Chiba 278, Japan; Eng.) -M. Paetzel 44-081