Structure–Activity Relationship Studies of Coumarin-like Diacid Derivatives as Human G Protein-Coupled Receptor-35 (hGPR35) Agonists and a Consequent New Design Principle

A series of coumarin-like diacid
derivatives were designed and
synthesized as novel agonists of human G-protein-coupled receptor
35 (hGPR35). Active compounds were characterized to possess one acidic
group on both sides of a fused tricyclic aromatic scaffold. Most of
them functioned as full agonists selective to hGPR35 and exhibited
excellent potency at low nanomolar concentrations. Substitution on
the middle ring of the scaffold could effectively regulate compound
potency. Structure–activity relationship studies and docking
simulation indicated that compounds that carried two acidic groups
with a proper special distance and attached to a rigid aromatic scaffold
would most likely show a potent agonistic activity on hGPR35. Following
this principle, we screened a list of known compounds and some were
found to be potent GPR35 agonists, and compound 24 even
had an EC50 of 8 nM. Particularly, a dietary supplement
pyrroloquinoline quinone (PQQ) was identified as a potent agonist
(EC50 = 71.4 nM). To some extent, this principle provides
a general strategy to design and recognize GPR35 agonists.