Optimization of Single Relaxin B-Chain Peptide Leads to the Identification of R2R01, a Potent, Long-Acting RXFP1 Agonist for Cardiovascular and Renal Diseases

Peptide 1, a C18 fatty acid-modified single-chain relaxin analogue, was recently identified as a potent, selective, and long-lasting relaxin family peptide receptor 1 (RXFP1) agonist. Further advanced pharmacokinetic profiling of this compound highlighted elevated levels of oxidative metabolism occurring in dogs and mini pigs but only marginally in rats. This study aimed to design long-lasting relaxin analogues with increased stability against metabolic oxidation while securing subnanomolar RXFP1 potency. Key structural elements, including fatty acid chain length, attachment position, and linker structure, were modified to reduce oxidative metabolism and improve pharmacokinetic parameters. Additionally, incorporating α-methyl lysine (Mly) at position 30, alongside other selective sequence mutations, resulted in several analogues with subnanomolar RXFP1 potency and improved duration of action compared to 1. Compound 21 (R2R01) was then selected as a candidate for an in-depth characterization. It is currently undergoing phase 2 clinical development for renal and cardiovascular diseases.