Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.

ABSTRACT: Antagonism of the human adenosine A₃ receptor (hA₃R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA₃R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA₃R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while su

SUBMITTER: Huang X 

PROVIDER: S-EPMC11320584 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature