GRK-biased adrenergic agonists for the treatment of type II diabetes and obesity

Biased agonism of G protein-coupled receptors (GPCRs) holds great promise for the development of safer medications. Current efforts have explored the balance between heterotrimeric G proteins and the scaffold protein b-arrestin; however, other transducers like GPCR kinases (GRKs) represent important, but understudied mediators of agonist-induced signaling. In particular, GRK2 has been shown to play an essential role in b2 adrenergic receptor (b2AR)-mediated glucose uptake, but b2AR agonists are generally thought to make poor clinical candidates for glycemic management given their potential for Gs/cAMP-induced cardiac side effects and tendency for b-arrestin-dependent desensitization with long-term treatment. For these reasons, we sought to develop pathway-selective agonists of b2AR that prefer GRK coupling to heterotrimeric Gs and b-arrestin. Ligand-based virtual screening and chemical evolution of adrenergic agonists led to the identification of GRK-biased b2AR partial agonists. We demonstrate that these compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared to standard b2-receptor agonists and incretin mimetics respectively. Furthermore, our lead candidate showed favorable pharmacokinetics and was determined to be safe in a placebo-controlled clinical trial. GRK-biased b2AR partial agonists are thus promising candidates to offer a viable, orally available alternative to injection-based incretin mimetics used in the treatment of type II diabetes and obesity.