Structure-Activity Relationships of Highly Potent and Selective A2B Adenosine Receptor Agonists

  • J Med Chem. 2025 Nov 13;68(21):22348-22365. doi: 10.1021/acs.jmedchem.5c01283.
Christopher J Smedley  1 ,  Jon Kyle Awalt  1 ,  Anh T N Nguyen  2 ,  Bing H Wang  3 ,  Arthur Christopoulos  2  4  5 ,  Manuela Jörg  1 ,  Lauren T May  2 ,  Peter J Scammells  1
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 3. School of Translational Medicine, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, VIC 3004, Australia.
  • 4. Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 5. Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
PMID: 41129794 DOI: 10.1021/acs.jmedchem.5c01283
Abstract

A series comprised of N6-substituted adenosines designed from the A2B adenosine agonist 4 were synthesized and their A2BR potency was assessed in a cAMP accumulation assay using FlpINCHO cells stably expressing the human A2BR. This study identified 12 novel A2BR agonists which exhibited subnanomolar potency at the A2BR. The most potent compounds possessed a 5'-N-ethyl carboxamide moiety (7, pEC50 = 10.24) or a slightly shorter N6-alkyl linker (8, pEC50 = 10.17) relative to 4. Both compounds were also highly receptor subtype selective versus the A1R, A2AR, and A3R. In terms of cellular activity, both the parent 4 and the 5'-N-ethyl carboxamide 7 ameliorated AngII stimulating effects in both cardiac myocytes and fibroblasts. Furthermore, compounds 4 and 7 attenuated TGFβ-stimulated Collagen synthesis in cardiac fibroblasts. These antihypertrophy and antifibrotic effects suggest that selective A2BR compounds may have therapeutic potential for Cardiovascular Disease where cardiac remodeling is a major driver.

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