Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure–Activity Relationships and Optimization

[Image: see text] 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 (AM(1)) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM(2)) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM(2) receptors would be therapeutically valuable, inhibition of AM(1) 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 AM(2) receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM(1) receptor. These results highlight the therapeutic potential of AM(2) antagonists.