6xz8

Structure of aldosterone synthase (CYP11B2) in complex with N-[(1R)-1-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]ethyl]methanesulfonamide

spinqualitylabelsall models 6xz8, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: HEC, O4T Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Aldosterone synthase (CYP11B2) inhibitors were explored in recent years as an alternative therapeutic option to MR antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including heart, vasculature, kidney, and CNS. A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 44, in an in vivo cynomolgus monkey acute ACTH challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1. Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors.,Liu Y, Wu J, Zhou M, Chen W, Li D, Wang ZG, Hornsperger B, Aebi JD, Marki HP, Kuhn B, Wang L, Kuglstatter A, Benz J, Muller S, Hochstrasser R, Ottaviani G, Xin J, Kirchner S, Mohr S, Verry P, Riboulet W, Shen HC, Mayweg AV, Amrein K, Tan X J Med Chem. 2020 Jun 12. doi: 10.1021/acs.jmedchem.0c00233. PMID:32530624 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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