Characterization of New PPARγ Agonists: Benzimidazole Derivatives – the Importance of Position 2

Abstract

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).

Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity

“…The compounds from this cluster follow the same pattern as cluster 1, but without the presence of an indole group. The sar8 [25], sar9 [26] and sar10 [27] series form cluster 4. The compounds from this cluster are derivatives of telmisartan, a compound that, in addition to being a PPARc partial agonist, is also a selective angiotensin II AT1 receptor blocker.…”

“…Binding features of partial agonists A total of 205 structures of PPARc agonists were retrieved from 12 SAR studies (sar1-12) of synthetic PPARc agonists (Table 1) [18][19][20][21][22][23][24][25][26][27][28][29]. Based on their chemical similarities, these 205 compounds can be grouped into five clusters (Fig.…”

“…A dataset of 205 PPARc agonists with measured IC 50 values (i.e., binding affinity measured by the displacement of a radiolabeled full agonist) and transactivation activity was assembled from several SAR studies [18][19][20][21][22][23][24][25][26][27][28][29] (see Table 1). The IC 50 (nM) values were then transformed to -log IC 50 (pIC 50 ) (see Supporting Information Table S1).…”

Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

“…On the other hand, valsartan has a biphenyl-tetrazole group, but no imidasole groups. Goebel et al (46,47) also demonstrated the structural characterization of a PPARγ-activating ARB, telmisartan, and they showed that valsartan has no structure that docks to PPARγ. In general, all ARBs have similar structures, but a small structural difference may be important with respect to the PPARγ-activating property.…”

Characterization of new PPARγ agonists: Benzimidazole derivatives—importance of positions 5 and 6, and computational studies on the binding mode

“…12 Furthermore, the alkyl chain in position 2 of the benzimidazole core, especially the propyl group, was important for potency and activation. 13 In continuation of our studies we investigated the significance of the positions 5 and 6 of the benzimidazole for PPARc modulating activity.…”