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

被引：0

作者：

Mallart, Sergio ^{[1
]}

Ingenito, Raffaele ^{[5
,8
]}

Magotti, Paola ^{[5
,9
]}

Bresciani, Alberto ^{[6
,10
]}

Di Marco, Annalise ^{[7
]}

Esposito, Simone ^{[7
,11
]}

Monteagudo, Edith ^{[7
,12
]}

Caretti, Fulvia ^{[7
]}

Orsatti, Laura ^{[7
]}

Santoprete, Alessia ^{[5
]}

Roversi, Daniela ^{[5
,13
]}

Tucci, Federica ^{[5
]}

Veneziano, Maria ^{[7
]}

Brasseur, Denis ^{[1
]}

Chenede, Xavier ^{[2
]}

Corbier, Alain ^{[2
]}

Gauzy-Lazo, Laurence ^{[1
]}

Gervat, Vincent ^{[1
]}

Marguet, Frank ^{[1
]}

Minoletti, Claire ^{[1
]}

Pasquier, Olivier ^{[3
]}

Poirier, Bruno ^{[2
]}

Azam, Aurelien ^{[4
]}

Maillere, Bernard ^{[4
]}

Bianchi, Elisabetta ^{[5
]}

Janiak, Philip ^{[2
]}

Duclos, Olivier ^{[1
]}

Illiano, Stephane ^{[2
]}

机构：

[1] Sanofi R&D, Integrated Drug Discovery, F-94400 Vitry Sur Seine, France

[2] Sanofi R&D, Cardiovasc & Metab, 13 Quai Jules Guesde, F-94400 Vitry Sur Seine, France

[3] Sanofi R&D, DMPK France, F-94400 Vitry Sur Seine, France

[4] Univ Paris Saclay, CEA, INRAE, Dept Medicaments & Technol Sante, F-91190 Gif Sur Yvette, France

[5] IRBM SpA, Peptides & Small Mol R&D Dept, I-00071 Rome, Italy

[6] IRBM SpA, Dept Translat Biol, I-00071 Pomezia, Italy

[7] IRBM SpA, Expt Pharmacol, I-00071 Pomezia, Italy

[8] Naturamla Srl, Via Monte Zebio 43, I-00195 Rome, Italy

[9] Zealand Pharm AS, Sydmarken 11, DK-2860 Soborg, Denmark

[10] Recursion, Schrodinger Bldg,Heatley Rd,Oxford Sci Pk, Oxford OX4 4GE, England

[11] Selvita SA, Podole 79, PL-30394 Krakow, Poland

[12] CHDI Management CHDI Fdn, Los Angeles, CA USA

[13] Univ Roma Tor Vergata, Via Ric Sci 1, Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 03期

关键词：

RECOMBINANT HUMAN RELAXIN; PROTEIN-COUPLED RECEPTOR; VASODILATION; SERELAXIN; ROLES; RAT;

D O I：

10.1021/acs.jmedchem.4c03085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 alpha-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.

引用

页码：3873 / 3885

页数：13

共 2 条

[1] R2R01: A long-acting single-chain peptide agonist of RXFP1 for renal and cardiovascular diseases
Poirier, Bruno
Pasquier, Olivier
Chenede, Xavier
Corbier, Alain
Prigent, Philippe
Azam, Aurelien
Bernard, Carine
Guillotel, Michel
Gillot, Florence
Riva, Laurence
Briand, Veronique
Ingenito, Raffaele
Gauzy-Lazo, Laurence
Duclos, Olivier
Philippo, Christophe
Maillere, Bernard
Bianchi, Elisabetta
Mallart, Sergio
Janiak, Philip
Illiano, Stephane
BRITISH JOURNAL OF PHARMACOLOGY, 2024, 181 (13) : 1993 - 2011
[2] Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases
Mallart, Sergio
Ingenito, Raffaele
Bianchi, Elisabetta
Bresciani, Alberto
Esposito, Simone
Gallo, Mariana
Magotti, Paola
Monteagudo, Edith
Orsatti, Laura
Roversi, Daniela
Santoprete, Alessia
Tucci, Federica
Veneziano, Maria
Bartsch, Regine
Boehm, Claudius
Brasseur, Denis
Bruneau, Patricia
Corbier, Alain
Froissant, Jacques
Gauzy-Lazo, Laurence
Gervat, Vincent
Marguet, Frank
Menguy, Isabelle
Minoletti, Claire
Nicolas, Marie-Francoise
Pasquier, Olivier
Poirier, Bruno
Raux, Alexandre
Riva, Laurence
Janiak, Philip
Strobel, Hartmut
Duclos, Olivier
Illiano, Stephane
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (04) : 2139 - 2150

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