Discovery, optimization, and biological activity of the first potent and selective small-molecule agonist series of human relaxin receptor 1 (RXFP1)

The peptide hormone relaxin has been clinically investigated as a beneficial treatment for acute heart failure (AHF). Relaxin has been shown to reduce blood pressure and promote vascular compliance in clinical studies, in addition to being able to remodel heart lesions. The target of relaxin’s action is the class A G-protein coupled receptor RXFP1. Here we present the discovery of the first small-molecule agonists of RXFP1 disclosed in the literature. Optimized compounds from this series are potent and highly selective RXFP1 agonists with similar efficacy as the natural hormone in functional assays. These molecules are easy to synthesize and the represented analog ML290 showed excellent absorption, distribution, metabolism, and excretion (ADME) data and pharmacokinetic (PK) properties. From our studies, we conclude that this probe, ML290, should be a very useful tool for the study of RXFP1 activation in pre-clinical disease models of heart failure and other diseases, and might provide a lead for the development of a small-molecule drug as an alternative to the current expensive recombinant human relaxin therapy.