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

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.

B类G蛋白偶联受体（GPCRs）在药物研发领域尚未得到充分挖掘。其中，降钙素受体（CTR）家族尤为具有挑战性，因为其受体由两种不同的成分组成异聚体：降钙素受体样受体（CLR）或降钙素受体（CTR）与三种被称为受体活性调节蛋白（RAMPs）的辅助蛋白之一。CLR/RAMP1构成CGRP受体，CLR/RAMP2构成肾上腺髓质素-1（AM1）受体，而CLR/RAMP3构成肾上腺髓质素-2（AM2）受体。CTR/RAMP复合物形成三种不同的胰岛素原受体。尽管选择性阻断AM2受体在治疗学上具有价值，但AM1受体的抑制将导致临床上难以接受的血压升高。本研究系统地研究了结构-活性关系，并导致了同类首创的AM2受体拮抗剂的开发。这些化合物表现出治疗学上宝贵的特性，其对AM1受体的选择性超过1000倍。这些结果突出了AM2拮抗剂在治疗学上的潜在价值。