title: Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome.
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).
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Cassia S
authors.initials: CS
authors.lastname: Mizuno
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.forename: Falgun H
authors.initials: FH
authors.lastname: Shah
authors.forename: Akshay
authors.initials: A
authors.lastname: Patny
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Kurtz
authors.forename: Harrihar A
authors.initials: HA
authors.lastname: Pershadsingh
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.forename: Vardan T
authors.initials: VT
authors.lastname: Karamyan
authors.forename: Paulo B
authors.initials: PB
authors.lastname: Carvalho
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015195:Drug Design; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D024821:Metabolic Syndrome; D008956:Models, Chemical; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II