A.Santopretea, S.Mallartd, E. Bianchia R.Ingenitoa, P.Magottia, A.Brescianib, A.Di Marcoc, S.Espositoc, E.Monteagudoc, F.Carettic, L.Orsattic, D.Roversia, A.Santopretea, F.Tuccia, M.Venezianoc, D.Brasseurd, X.Chénédee, A.Corbiere, L.Gauzy Lazod, V.Gervatd, F.Marguetd, C.Minolettid, O.Pasquierf, B. Poiriere, A.Azame, P.Janiake, O.Duclosd, S.Illianoeg
IRBM, aPeptide Chemistry, bTranslational Biology cExperimental Pharmacology, Pomezia, Italy; Sanofi R&D, dIntegrated Drug Discovery, eCardio-Vascular and Metabolism, fDMPK, Investigative Toxicology Pre Clinical Safety Franceg Chilly Mazarin 91385 and Vitry sur Seine 94400, France
Targeting the relaxin family peptide receptor 1 (RXFP1) represents a promising strategy for the treatment of cardiovascular and renal diseases. We report the development of R2R01, a novel, long-acting peptide agonist engineered for high potency, extended half-life, and improved translational potential. Initial discovery efforts identified a C18 fatty acid–modified single-chain analogue of relaxin-2 (chain B) as a potent and selective RXFP1 agonist with favourable pharmacokinetic (PK)1-2 properties. However, advanced PK profiling of this compound highlighted elevated levels of oxidative metabolism occurring in dogs and minipigs, limiting further advancement3.
Through an extensive optimization program, we addressed these metabolic liabilities while maintaining sub-nanomolar RXFP1 activity. Structure-activity relationship (SAR) studies focused on modifying key molecular features—including fatty acid chain length, conjugation site, and linker composition. Notably, the introduction of α-methyl-lysine at position 30, along with additional stabilizing modifications, yielded analogs with enhanced metabolic stability, prolonged in vivo activity, and a significant reduction in mast cell–mediated pseudo-allergic reactions4.
R2R01 emerged as the lead candidate from this optimized series, exhibiting a best-in-class profile in terms of receptor potency, duration of action, and preclinical safety. Its development exemplifies the power of an integrated discovery platform combining rational design, high-throughput screening, and translational in vivo models to accelerate peptide therapeutic innovation. R2R01 is currently undergoing Phase 2 clinical evaluation in patients with heart failure and hepatorenal syndrome5, supporting its potential as a transformative therapy in areas of high unmet medical need.
1S.Mallart et al. J. Med. Chem. 2021, 64(4):2139-2150, 2S.Illiano et al. Sci. Rep. 2022, 12(1):20435, 3 S.Esposito. J. Pharm. Biomed. Anal. 2023, 227, 115256, 4S.Mallart et al. J. Med. Chem. 2025, 68, 3, 3873-3885, 5B.Poirier. Br. J. Pharmacol. 2024