3R8A

X-ray crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a compound with dual PPAR gamma agonism and Angiotensin II Type I receptor antagonism activity

Summary for 3R8A

• Entry DOI: 10.2210/pdb3r8a/pdb
• Related: 2Q8S 3IA6
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-ethyl-5,7-dimethyl-3-{(1S)-5-[2-(1H-tetrazol-5-yl)phenyl]-2,3-dihydro-1H-inden-1-yl}-3H-imidazo[4,5-b]pyridine (3 entities in total)
• Functional Keywords: nuclear hormone activator, angiotensin ii type i receptor antagonist, ligand bound structure, diabetes mellitus, metabolic syndrome, obesity, nuclear protein
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 65530.15

Authors

Ohren, J.F. (deposition date: 2011-03-23, release date: 2012-03-14, Last modification date: 2023-09-13)

Primary citation

Casimiro-Garcia, A.,Filzen, G.F.,Flynn, D.,Bigge, C.F.,Chen, J.,Davis, J.A.,Dudley, D.A.,Edmunds, J.J.,Esmaeil, N.,Geyer, A.,Heemstra, R.J.,Jalaie, M.,Ohren, J.F.,Ostroski, R.,Ellis, T.,Schaum, R.P.,Stoner, C.
Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-gamma.
J.Med.Chem., 54:4219-4233, 2011

PubMed 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.

PubMed: 21557540
DOI: 10.1021/jm200409s

Experimental method

X-RAY DIFFRACTION (2.41 Å)