Characterization of new PPARgamma agonists: benzimidazole derivatives - the importance of position 2.

Probing SAR: The 1-(biphenyl-4-ylmethyl)-1H-benzo[d]imidazole moiety is known to be an essential structural component of telmisartan for PPARgamma activation. This study focused on the substituents at position 2 of the benzimidazole in an attempt to optimize PPARgamma activation. In particular, the elongation of the alkyl chain and the introduction of an aromatic ring system were studied (shown).The relevance of substituents at C-2 of the central benzimidazole of telmisartan for PPARgamma activation has recently been demonstrated, and the most active compound identified in our previous work, 4'-[(2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (4 a), is used as lead structure in the present study. Modifications at C-2 included butyl (4 b), iso-butyl (4 c), tert-butyl (4 d), phenyl (4 e), benzyl (4 f), phenethyl (4 g), 4-chlorobenzyl (4 h), 4-methoxyphenyl (4 i), and 4-hydroxyphenyl (4 j) moieties. The compounds were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay with COS-7 cells, transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARgamma activation. The activity in the luciferase assay increased in the alkyl series: propyl (4 a) <iso-butyl (4 c) <or= tert-butyl (4 d) <butyl (4 b). A phenyl group at C-2 led to the most active compound (4 e) in this study with an EC(50) value of 0.27 microM. 4-Hydroxylation of the C-2 phenyl group (4 j) drastically decreased the activity (EC(50)=5.8 microm) presumably due to hydrophilic repulsion. This assumption was verified by O-methylation to give compound 4 i, which maintained activity (EC(50)=0.29 microM). The weak effect of the benzyl derivative 4 f (EC(50)=1.4 microM) was abolished by an additional hydrophobic 4-chloro substituent (4 h; EC(50)=0.55 microM) or an elongation of the alkyl chain between the phenyl and the benzimidazole core (4 g; EC(50)=0.31 microM).