2. Academic Validation
  3. Optimization of Single Relaxin B-Chain Peptide Leads to the Identification of R2R01, a Potent, Long-Acting RXFP1 Agonist for Cardiovascular and Renal Diseases

Optimization of Single Relaxin B-Chain Peptide Leads to the Identification of R2R01, a Potent, Long-Acting RXFP1 Agonist for Cardiovascular and Renal Diseases

  • J Med Chem. 2025 Feb 13;68(3):3873-3885. doi: 10.1021/acs.jmedchem.4c03085.
Sergio Mallart 1,  Raffaele Ingenito 2,  Paola Magotti 2,  Alberto Bresciani 3,  Annalise Di Marco 4,  Simone Esposito 4,  Edith Monteagudo 4,  Fulvia Caretti 4,  Laura Orsatti 4,  Alessia Santoprete 2,  Daniela Roversi 2,  Federica Tucci 2,  Maria Veneziano 4,  Denis Brasseur 1,  Xavier Chénedé 5,  Alain Corbier 5,  Laurence Gauzy-Lazo 1,  Vincent Gervat 1,  Frank Marguet 1,  Claire Minoletti 1,  Olivier Pasquier 6,  Bruno Poirier 5,  Aurélien Azam 7,  Bernard Maillère 7,  Elisabetta Bianchi 2,  Philip Janiak 5,  Olivier Duclos 1,  Stephane Illiano 5
Affiliations

Affiliations

  • 1 Integrated Drug Discovery, Sanofi R&D, 13 quai Jules Guesde, Vitry sur Seine 94400, France.
  • 2 Peptides and Small Molecules R&D Department, IRBM, Spa, Via Pontina Km 30 600, Pomezia 00071, Italy.
  • 3 Department of Translational Biology, IRBM, Spa, Via Pontina Km 30 600, Pomezia 00071, Italy.
  • 4 Experimental Pharmacology, IRBM, Spa, Via Pontina Km 30 600, Pomezia 00071, Italy.
  • 5 Cardio-Vascular and Metabolism, Sanofi R&D, 13 quai Jules Guesde, Vitry sur Seine 94400, France.
  • 6 DMPK France, Sanofi R&D, 13 quai Jules Guesde, Vitry sur Seine 94400, France.
  • 7 CEA, INRAE, Département Médicaments et Technologies pour la Santé, Université de Paris-Saclay, SIMoS, Gif-sur-Yvette 91190, France.
PMID: 39888342 DOI: 10.1021/acs.jmedchem.4c03085
Abstract

Peptide 1, a C18 fatty acid-modified single-chain relaxin analogue, was recently identified as a potent, selective, and long-lasting relaxin family peptide receptor 1 (RXFP1) agonist. Further advanced pharmacokinetic profiling of this compound highlighted elevated levels of oxidative metabolism occurring in dogs and mini pigs but only marginally in rats. This study aimed to design long-lasting relaxin analogues with increased stability against metabolic oxidation while securing subnanomolar RXFP1 potency. Key structural elements, including fatty acid chain length, attachment position, and linker structure, were modified to reduce oxidative metabolism and improve pharmacokinetic parameters. Additionally, incorporating α-methyl lysine (Mly) at position 30, alongside Other selective sequence mutations, resulted in several analogues with subnanomolar RXFP1 potency and improved duration of action compared to 1. Compound 21 (R2R01) was then selected as a candidate for an in-depth characterization. It is currently undergoing phase 2 clinical development for renal and cardiovascular diseases.

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