Discovery of a first-in-class potent small molecule antagonist against the adrenomedullin-2 receptor

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumour progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same orphan G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). CLR with RAMP2 forms an adrenomedullin-1 receptor and CLR with RAMP3 forms an adrenomedullin-2receptor. Recent research suggests that selective blockade of adrenomedullin-2 receptors would be valuable therapeutically. Here we describe the design, synthesis and characterization of potent small molecule adrenomedullin-2 receptor antagonists with 1,000-foldselectivity over the adrenomedullin-1 receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties and inhibit xenograft tumour growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anti-cancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.