Development of activators for SERCA2a for heart failure treatments

  • Eur J Med Chem. 2026 Feb 5:303:118408. doi: 10.1016/j.ejmech.2025.118408.
Marzena Brinkmann  1 ,  Tsung-Yun Kent Wong  1 ,  Osha Roopnarine  2 ,  Samantha L Yuen  2 ,  Kaja Berg  1 ,  Razvan L Cornea  2 ,  Robyn T Rebbeck  3 ,  David D Thomas  4 ,  Courtney C Aldrich  5
Affiliations
  • 1. Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street S.E., Minneapolis, 55455, MN, USA.
  • 2. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, 55455, MN, USA.
  • 3. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, 55455, MN, USA. Electronic address: [email protected].
  • 4. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, 55455, MN, USA. Electronic address: [email protected].
  • 5. Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street S.E., Minneapolis, 55455, MN, USA. Electronic address: [email protected].
PMID: 41351919 DOI: 10.1016/j.ejmech.2025.118408
Abstract

The sarco/endoplasmic reticulum CA2+-ATPase (SERCA2a) is a central regulator of cardiac CA2+ handling and an emerging therapeutic target for heart failure. Here, we report a comprehensive structure-activity relationship (SAR) study around small-molecule activator compound 1, integrating CA2+-ATPase and CA2+-uptake assays, isoform selectivity profiling, and ADMET characterization across more than fifty analogues. Systematic modification of the left-hand aryl/heteroaryl region revealed a strong dependence of activity on aromaticity and lipophilicity, with CF3- and Br-substituted analogues providing substantial gains in potency. Optimization of the central amide linker established the importance of N-alkyl chain length, subtle hydrogen-bonding capacity, and a bent ligand geometry for productive SERCA2a engagement. Electronic tuning of the right-hand benzyl group further modulated efficacy, highlighting the essential contribution of an ortho-donor substituent. Functional evaluation across multiple CA2+ concentrations identified several analogues with ATPase activation but inhibitory CA2+-uptake effects, underscoring the need for dual-assay assessment to ensure bona fide activation. Among the series, compound 25 emerged as a balanced lead, displaying micromolar potency, robust concordant enhancement of ATPase and CA2+-uptake activity, favorable solubility, and improved cytotoxicity relative to compound 1. Collectively, these findings define key structural determinants governing SERCA2a activation and provide a rational framework for developing next-generation, drug-like cardiac SERCA2a modulators.

Keywords
ADMET; ATPase activity; Activators; Calcium uptake; Heart failure; SAR; SERCA2a.
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