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

• Published in: Bioorganic chemistry 2022-03, Vol.120, p.105635-105635, Article 105635
• Main Authors: Richards, Benjamin J., Glab, Jason A., Mbogo, George W., Dahanayake, Darani, Smith, Brian J., Puthalakath, Hamsa, Abbott, Belinda M.
• Format: Article
• Language: English
• Subjects: Azepanes; Bim; Drug discovery; Heart failure; Mouse embryonic fibroblasts
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105635

[Display omitted] •First example of compounds able to reduce Bim expression levels in a mouse embryonic fibroblast model.•Novel analogues have been designed and synthesised to generate a structure-activity relationship profile.•Analogues demonstrate strong reduction of Bim levels at a low micromolar level with low toxicity. 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.