The Discovery of C7-Substituted Norbornyl Bisamides as RXFP1 Small Molecule Agonists

Human relaxin-2 (relaxin, H2-RLX, RLN2), an endogenous hormone associated with mammalian pregnancy, and its cognate receptor relaxin family peptide receptor 1 (RXFP1) have been implicated as important modulators of cardiovascular function and agonism of RXFP1 may potentially be utilized for the treatment of heart failure. Exploration of chemical space around previously reported anthranilamide 2 led to the discovery of lead compound 39 with significantly improved agonist activities toward human and rodent RXFP1. Compound 39 induced a dose-dependent heart rate increase in isoflurane-anesthetized naïve rats, which is consistent with the hemodynamic profile of relaxin in rat. Compound 39 also elicited significant interpubic ligament (IPL) expansion in C57BL/6 mouse, measured with microCT imaging, which recapitulated the effect of relaxin.