6xz8
From Proteopedia
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
Structural highlights
Disease[C11B2_HUMAN] Familial hyperreninemic hypoaldosteronism type 1;Familial hyperaldosteronism type I. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2. Function[C11B2_HUMAN] Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.[1] Publication Abstract from PubMedAldosterone 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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