1244012-44-9

Upstream product

• 108-36-1 1,3-dibromobenzene 
• 5228-61-5 5-bromo-2-nitroaniline 
• 51686-78-3 2,4-dibromonitrobenzene 
• 1842-76-8 6-bromo-2-propyl-1H-benzo[d]imidazole 
• 114772-54-2 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 

Downstream Products

• 1244012-15-4 4’-((5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid 
• 1422043-25-1 C₃₂H₂₆N₂O₃ 
• 1422043-23-9 C₃₂H₂₆N₂O₂S 
• 1433222-09-3 4-[(5-(1-benzothiophen-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2'-carbonitrile 

Relevant academic research and scientific papers

Importance of 5/6-aryl substitution on the pharmacological profile of 4?-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1?-biphenyl]-2-carboxylic acid derived PPARγ agonists

In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPARγ agonist 4‘-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1‘-biphenyl]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPARγ activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain. Partial agonists with higher potency than telmisartan or the lead were obtained with OH or Cl substituents at the phenyl ring. Molecular modeling suggested additional hydrogen or halogen bonds with Phe360 located at helix 7. It is assumed that these interactions fix helix 7, thereby promoting a partial agonist conformation of the receptor. The theoretical considerations correlate very well with the results from the luciferase transactivation assay using hPPARγ-LBD as well as those from a time-resolved fluorescent resonance energy transfer (TR-FRET) assay in which the coactivator (TRAP220, PGC-1α) recruitment and corepressor (NCoR1) release pattern was investigated.

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

In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARγ activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl)methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARγDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARγ activation. An enhanced effect on PPARγ activation could be observed if lipophilic moieties are introduced in these positions. 4′-[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2- carboxylic acid (5) was identified as the most potent compound with an EC 50 of 0.26 μM and the profile of a full agonist. Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments.