Oral delivery of G protein-coupled receptor modulators: an explanation for the observed class difference

G protein-coupled receptors (GPCRs) represent important targets for drug intervention. However, analysis of GPCR modulator drugs exhibits an important class difference, with many drugs available against aminergic GPCR targets, but relatively few against non-aminergic targets. The reason for this is that commonly drugs mimic the physicochemistry of the receptor ligand. Aminergic ligands generally exhibit physicochemical properties (molecular weight, lipophilicity and hydrogen bonding potential) that are consistent with extensive oral absorption. In contrast, non-aminergic ligands generally exhibit physicochemical properties that are at odds with oral delivery. Thus, combining required potency versus the receptor, with oral delivery potential is a significant challenge, and drug discovery becomes a question of finding the exceptional compound that lies at the edge of ADME space.