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 <b>2</b> led to the discovery of lead compound <b>39</b> with significantly improved agonist activities toward human and rodent RXFP1. Compound <b>39</b> induced a dose-dependent heart rate increase in isoflurane-anesthetized naïve rats, which is consistent with the hemodynamic profile of relaxin in rat. Compound <b>39</b> also elicited significant interpubic ligament (IPL) expansion in C57BL/6 mouse, measured with microCT imaging, which recapitulated the effect of relaxin.
Authors
- Ruth R. Wexler (ORCID: https://orcid.org/0000-0001-5514-5053)
- Lei Zhao (ORCID: https://orcid.org/0000-0001-5027-2379)
- R. CHEN
- R. Michael Lawrence
- Arvind Mathur (ORCID: https://orcid.org/0000-0003-3146-8485)
- Claudia Generaux (ORCID: https://orcid.org/0000-0002-8516-9467)
- Donna M. Bilder
- Michael A. Galella
- Michael C. Myers (ORCID: https://orcid.org/0000-0002-7895-1397)
- Thomas Petrone
- Carol S. Ryan
- Todd J. Friends
- Adam Clarke
- Shun Su (ORCID: https://orcid.org/0000-0001-8100-9645)
- Jeff Bostwick
- Franck Duclos (ORCID: https://orcid.org/0000-0002-9519-4076)
- Anne Rose
- Yixin Li (ORCID: https://orcid.org/0000-0001-8740-5040)
- Jianqing Li (ORCID: https://orcid.org/0000-0002-8445-9796)
- Matthew Fronheiser
- Cort S. Madsen
- Carol Krause
Institutions
- Bristol-Myers Squibb (Germany) (DE)
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb (Sweden) (SE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00991
- Citations
- 2
- Primary Topic
- Pregnancy-related medical research
- Type
- article
- Field-Weighted Citation Impact
- 3.76