title: Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.
abstract: A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.
authors.affiliation: Drug Discovery Research, Astellas Pharma, Inc., Ibaraki, Japan (H.K., E.K., T.N., K.G., Y.K., A.S., K.H., T.Y., M.S., Y.T., M.O.);Medical Affairs, Astellas Pharma, Inc., Tokyo, Japan (H.O.); Shizuoka Prefectural General Hospital, Shizuoka, Japan (T.Y.); and Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (H.M.).
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kakuta
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Gato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Suwa
authors.forename: Kazuya
authors.initials: K
authors.lastname: Honbou
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okumura
authors.forename: Masanao
authors.initials: M
authors.lastname: Sanagi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Takako
authors.initials: T
authors.lastname: Yonemoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002151:Calorimetry; D002454:Cell Differentiation / Q000187:drug effects; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D008567:Membranes, Artificial; D047495:PPAR gamma; D000077333:Telmisartan