Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome
Document Type
Article
Publication Date
2-11-2010
Publication Title
Journal of Medicinal Chemistry
ISSN
0022-2623
Volume
53
Issue/No.
3
First Page
1076
Last Page
85
Abstract
In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM).
NSUWorks Citation
Mizuno, Cassia S.; Chittiboyina, Amar G.; Shah, Falgun H.; Patny, Akshay; Kurtz, Theodore W.; Pershadsingh, Harrihar A.; Speth, Robert C.; Karamyan, Vardan T.; Carvalho, Paulo B.; and Avery, Mitchell A., "Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome" (2010). HPD Articles. 94.
https://nsuworks.nova.edu/hpd_facarticles/94
ORCID ID
0000-0002-6434-2175
DOI
10.1021/jm901272d
Copyright
Copyright © 2010 American Chemical Society
