ABSTRACT
Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phaseâ II trial.
Subject(s)
Heart Failure/drug therapy , Kidney Diseases/drug therapy , Mineralocorticoid Receptor Antagonists/chemistry , Naphthyridines/chemistry , Receptors, Mineralocorticoid/chemistry , Animals , Binding Sites , Chronic Disease , Computer Simulation , Drug Evaluation, Preclinical , Heart Failure/complications , Humans , Kidney Diseases/complications , Mineralocorticoid Receptor Antagonists/chemical synthesis , Mineralocorticoid Receptor Antagonists/therapeutic use , Naphthyridines/chemical synthesis , Naphthyridines/therapeutic use , Potassium/urine , Protein Structure, Tertiary , Rats , Receptors, Mineralocorticoid/metabolism , Sodium/urineABSTRACT
[Reaction: see text]. A regioselective and efficient approach toward 6-amino-5-benzoyl-1-substituted 2(1H)-pyridinones by reaction of acyclic ketene aminals with propiolic acid ester was developed. The effect of the solvent and temperature on the regioselectivity of the reaction and the compatibility of the target compounds to functional group manipulations was examined. Substrates with an ortho substituent build atropisomers due to the restricted rotation around the C-N bond. The enantiomers were separated, and the barrier of rotation was determined experimentally. Quantum chemical calculations allowed a ranking of the barrier heights, and a new mechanism of rotation by deformation of the central pyridinone moiety is proposed.
Subject(s)
Pyridones/chemical synthesis , Models, Chemical , Molecular Conformation , Molecular Structure , StereoisomerismABSTRACT
Novel cyclohexadienes have been identified as potent and specific IK(Ca)-channel blockers. In this communication we describe their synthesis as well as their chemical and biological properties. A selected derivative is being enriched in rat brain and reduces the infarct volume, intracranial pressure as well as the water content in a rat subdural hematoma model of traumatic brain injury after iv administration.
