Discovery of BE2012, a First-in-Class REV-ERBα/β Antagonist with Favorable Selectivity and Pharmacokinetics, and In Vivo Efficacy in Inducing Key Myogenic Factors for Muscle Repair upon Acute Muscle Injury.

REV-ERBα is a nuclear receptor transcriptional repressor involved in circadian rhythm, metabolism, inflammation, and myogenesis. Antagonizing REV-ERBα has emerged as a promising therapeutic strategy, yet few compounds with favorable pharmacokinetic profiles have been identified since SR8278. Here, we report the discovery and optimization of BE2012, a 3-aminoquinazolinone antagonist identified through high-throughput screening and refined via systematic structure-activity relationship studies. BE2012 exhibited potent REV-ERBα antagonism (EC50 = 0.285 μM), high nuclear receptor selectivity, minimal CNS off-target interactions, and improved ADME and pharmacokinetic properties, including a 22-fold longer half-life (t1/2 = 3.79 h) than SR8278. Molecular modeling revealed key hydrophobic and hydrogen-bonding interactions within the REV-ERBα ligand-binding pocket that stabilize BE2012 and explain its enhanced potency. In a murine model of acute muscle injury, BE2012 upregulated myogenic transcription factors and promoted muscle repair. Collectively, BE2012 represents a selective, pharmacokinetically favorable REV-ERBα/β antagonist with therapeutic potential in muscle regeneration and related diseases.

• Publication year

  2025

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2025-12-23

• Fields of study

  Medicine

• Identifiers
  DOI 10.1021/acs.jmedchem.5c02749PMID 41432990
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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