Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure-Activity...

Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM₁) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM₂) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM₂ receptors would be therapeutically valuable, inhibition of AM₁ receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure-activity relationships that has led to the development of first-in-class AM₂ receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM₁ receptor. These results highlight the therapeutic potential of AM₂ antagonists.