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.