2. Academic Validation
  3. Discovery, synthesis and exploration of N-benzylsulfonyl-2-phenylazepanes as inhibitors of Bim expression in a mouse embryonic fibroblast model

Discovery, synthesis and exploration of N-benzylsulfonyl-2-phenylazepanes as inhibitors of Bim expression in a mouse embryonic fibroblast model

  • Bioorg Chem. 2022 Mar;120:105635. doi: 10.1016/j.bioorg.2022.105635.
Benjamin J Richards 1,  Jason A Glab 2,  George W Mbogo 2,  Darani Dahanayake 1,  Brian J Smith 1,  Hamsa Puthalakath 2,  Belinda M Abbott 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
  • 2 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
  • 3 Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. Electronic address: [email protected].
PMID: 35124512 DOI: 10.1016/j.bioorg.2022.105635
Abstract

Chronic activation of beta-adrenergic receptors by the sympathetic nervous system results in the Apoptosis of cardiomyocytes. Due to the inability of cardiomyocytes to regenerate, this can result in heart failure. Upregulation of the pro-apoptotic protein Bim has been implicated as the cause of cardiomyocyte Apoptosis. Beta blockers are the frontline drug used to negate this apoptotic pathway, as no direct inhibitors of Bim expression currently exist. Unfortunately, treatment of heart failure using beta blockers is not optimal. Therefore, direct inhibition of Bim expression is an attractive strategy to provide protection against stress-induced Apoptosis of cardiomyocytes. Herein we explore a class of N-benzylsulfonyl-2-phenylazepanes to obtain anti-apoptotic compounds capable of reducing Bim expression levels to 7% of the control at 10 μM in cardiomyocytes under conditions of chronic beta-adrenergic receptor activation with little inhibitory effect upon protein kinase A activity and minimal toxicity.

Keywords

Azepanes; Bim; Drug discovery; Heart failure; Mouse embryonic fibroblasts.

Figures
Products