Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors
- 12 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (13), 6876-6897
- https://doi.org/10.1021/acs.jmedchem.0c00233
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 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.Funding Information
- F. Hoffmann-La Roche
This publication has 29 references indexed in Scilit:
- The past, present and future of renin–angiotensin aldosterone system inhibitionInternational Journal of Cardiology, 2013
- Eplerenone in Patients with Systolic Heart Failure and Mild SymptomsNew England Journal of Medicine, 2011
- Aldosterone Synthase Inhibition With LCI699Hypertension, 2010
- Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)Journal of Medicinal Chemistry, 2010
- Renin–Angiotensin System Blockade and Cardiovascular and Renal ProtectionThe American Journal of Cardiology, 2010
- Synthesis, Biological Evaluation, and Molecular Modeling of Abiraterone Analogues: Novel CYP17 Inhibitors for the Treatment of Prostate CancerJournal of Medicinal Chemistry, 2008
- The incidence and implications of aldosterone breakthroughNature Clinical Practice Nephrology, 2007
- Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial InfarctionNew England Journal of Medicine, 2003
- The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart FailureNew England Journal of Medicine, 1999
- Association of the Renin-Sodium Profile with the Risk of Myocardial Infarction in Patients with HypertensionNew England Journal of Medicine, 1991