6XZ9
Structure of aldosterone synthase (CYP11B2) in complex with 5-chloro-3,3-dimethyl-2-[5-[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxy-3-pyridyl]isoindolin-1-one
Summary for 6XZ9
| Entry DOI | 10.2210/pdb6xz9/pdb |
| Related | 6XZ8 |
| Descriptor | Cytochrome P450 11B2, mitochondrial, HEME C, 5-chloranyl-3,3-dimethyl-2-[5-[1-(1-methylpyrazol-4-yl)carbonylazetidin-3-yl]oxypyridin-3-yl]isoindol-1-one, ... (4 entities in total) |
| Functional Keywords | cytochrome p450, cyp11b2, aldosterone synthase, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 3 |
| Total formula weight | 171937.82 |
| Authors | Kuglstatter, A.,Joseph, C.,Benz, J. (deposition date: 2020-02-03, release date: 2020-06-24, Last modification date: 2024-05-01) |
| Primary citation | Liu, Y.,Wu, J.,Zhou, M.,Chen, W.,Li, D.,Wang, Z.,Hornsperger, B.,Aebi, J.D.,Marki, H.P.,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, H.C.,Mayweg, A.V.,Amrein, K.,Tan, X. Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors. J.Med.Chem., 63:6876-6897, 2020 Cited by PubMed Abstract: Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (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 , in an cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold selectivity against CYP11B1. PubMed: 32530624DOI: 10.1021/acs.jmedchem.0c00233 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.77 Å) |
Structure validation
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