Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-γ

Abstract

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

“…Unexpectedly in PPARγ interaction modes, the lipophilic tails (R 1 ) of 1, 8 and compound 19 were buried in AF-2 domain of the binding pocket, interacting with residues His323, Tyr327 and His449 through non-polar or van der Waals interactions as indicated in previous paper [17, 29]. Clearly, their interaction modes were substantially distinct from the typical PPARγ agonists, whose acid heads directly interacted with His323, Tyr327 and His449.…”

“…A set of imidazo-\ pyridines with dual activities towards AT1 antagonism (IC 50 : 0.49∼94.1 nM) and PPARγ partial activation (EC 50 : 20∼3640 nM) (Table 1) were collected from the published literatures [17, 29]. In the study, compounds with highly structural difference and no explicit activity values were excluded and not applied into the modeling.…”

“…The proteins for docking analysis were downloaded from RCSB Protein Data Bank (http://www.rcsb.org/pdb/home/home.do, PDB ID: 4ZUD for AT1, 3R8A for PPARγ) [17, 36]. All these compounds were docked into the receptor's active binding cavity.…”

“…Thiazolidinediones (TZDs, such as rosiglitazone and piglitazone) can greatly activate PPARγ. TZDs were first reported as insulin-sensitizing drugs in the early 1980s by the pharmaceutical company Takeda and developed for the treatment of type 2 diabetes mellitus in clinical practice [15–17]. However, the administration of TZDs could produce severe side effects such as fluid retention, weight gain, cardiac hypertrophy, bone fractures, and hepatotoxicity [18].…”

“…Series of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridin-4-one derivatives (Figure 2) were obtained by Agustin Casimiro-Garcia [17, 29] via maintaining the main scaffold of telmisartan. These compounds showed robust AT 1 antagonistic activity and partial activation of PPARγ.…”