Structure–Activity Relationship Studies toward the Optimization of First-In-Class Selective Small Molecule Agonists of the GPCR Relaxin/Insulin-like Family Peptide Receptor 2
A dose-response quantitative high-throughput screening of 147,334 small molecule compounds using a human Relaxin/Insulin-like Family Peptide Receptor 2 (RXFP2)-transfected HEK293T-RXFP2 cell line identified compound <b>5</b> with modest Insulin-Like3 (INSL3) agonist activity. An extensive structure-activity relationship (SAR) study was undertaken to improve potency, efficacy, and physical/metabolic properties of the series, resulting in the discovery of compound <b>68</b>. This compound represents the first-in-class small molecule full agonist of RXFP2 that exhibits nanomolar potency and favorable pharmacokinetic characteristics, including high systemic exposure in vivo. Based on these findings, compound <b>68</b> was selected as the lead preclinical candidate for investigating the role of RXFP2 activation in bone remodeling and other physiological systems in vitro and in vivo<i>.</i>
Authors
- Konstantinos Afratis (ORCID: https://orcid.org/0000-0003-4068-6900)
- Emmett R. George (ORCID: https://orcid.org/0000-0002-9026-9390)
- Irina U. Agoulnik (ORCID: https://orcid.org/0000-0003-4889-0324)
- María Esteban-López (ORCID: https://orcid.org/0000-0002-5897-3003)
- Christopher A. LeClair (ORCID: https://orcid.org/0000-0002-2746-5938)
- Marc Ferrer
- Wenjuan Ye
- Elias Carvalho Padilha (ORCID: https://orcid.org/0000-0002-3794-9389)
- Juan Marugán (ORCID: https://orcid.org/0000-0002-3951-7061)
- Elena Barnaeva
- David Calabrese (ORCID: https://orcid.org/0000-0001-8101-5391)
- Kenneth J. Wilson (ORCID: https://orcid.org/0000-0002-9679-1980)
- Mark J. Henderson (ORCID: https://orcid.org/0000-0001-8590-7338)
- Abhijeet Kapoor (ORCID: https://orcid.org/0000-0002-3606-3463)
- Samuel A. Kotler (ORCID: https://orcid.org/0000-0001-5420-9510)
- Pranav Shah (ORCID: https://orcid.org/0000-0003-0076-7159)
- Courtney B. Myhr
- Alexander Kushnir
- Yuhong Fang
- Curtis E. Moore
- Xin Hu
- Noel Southall
- Amy Wang
- Xin Xu
Institutions
- National Institutes of Health (US)
- Florida International University (US)
- University of South Florida (US)
- National Center for Advancing Translational Sciences (US)
- The Ohio State University (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-02-19
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03387
- Primary Topic
- Pregnancy-related medical research
- Type
- article
- Field-Weighted Citation Impact
- 0.00