Mineralocorticoid Receptor Antagonists.

Area of Science:

• Medicinal Chemistry and Pharmacology
• Drug Discovery and Development

Background:

• Two steroidal mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone, are FDA-approved.
• Non-steroidal MR antagonists are in clinical trials for heart failure, hypertension, and diabetic kidney disease.
• Preclinical studies explore structurally diverse chemical series for MR antagonism.

Purpose of the Study:

• To address the challenge of designing novel MR ligands with selectivity over other oxosteroid receptors (GR, PR, AR).
• To develop orally available MR antagonists despite the lipophilic nature of the MR binding pocket.
• To identify and optimize new chemical entities for therapeutic applications.

Main Methods:

• Utilized high-throughput screening (HTS) to identify novel starting points for drug discovery.
• Employed property-based drug design principles for ligand optimization.
• Leveraged protein-ligand X-ray crystallography to guide structure-based drug design.

Main Results:

• Successfully identified novel starting points through HTS.
• Optimized lead compounds using structure-based and property-based design strategies.
• Demonstrated feasibility of designing selective and orally available MR ligands.

Conclusions:

• High-throughput screening is a viable strategy for discovering novel mineralocorticoid receptor antagonists.
• Structure-based and property-based drug design are crucial for optimizing ligands for selectivity and pharmacokinetic properties.
• Advancements in ligand design hold promise for treating cardiovascular and kidney diseases.