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Optimization of fatty acid\u2010acetylated single\u2010chain peptide analogues of relaxin culminated in the design and synthesis of R2R01, a potent and selective RXFP1 agonist with subcutaneous bioavailability and extended half\u2010life.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cellular assays and pharmacological models of RXFP1 activation were used to validate the potency and selectivity of R2R01. Increased renal blood flow was used as a translational marker of R2R01 activity. Human mastocytes (LAD2 cells) were used to study potential pseudo\u2010allergic reactions and CD4+ T\u2010cells to study immunogenicity. The pharmacokinetics of R2R01 were characterized in rats and minipigs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In vitro, R2R01 had comparable potency and efficacy to relaxin as an agonist for human RXFP1. In vivo, subcutaneous administration of R2R01 increased heart rate and renal blood flow in normotensive and hypertensive rat and did not show evidence of tachyphylaxis. R2R01 also increased nipple length in rats, used as a chronic model of RXFP1 engagement. Pharmacokinetic studies showed that R2R01 has a significantly extended terminal half\u2010life. The in vitro assays with LAD2 cells and CD4+ T\u2010cells showed that R2R01 had low potential for pseudo\u2010allergic and immunogenic reactions, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications<\/jats:title><jats:p>R2R01 is a potent RXFP1 agonist with an extended half\u2010life that increases renal blood flow in various settings including normotensive and hypertensive conditions. The preclinical efficacy and safety data supported clinical development of R2R01 as a potential new therapy for renal and cardiovascular diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16338","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T11:08:38Z","timestamp":1709809718000},"page":"1993-2011","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["R2R01: A long\u2010acting single\u2010chain peptide agonist of RXFP1 for renal and cardiovascular diseases"],"prefix":"10.1111","volume":"181","author":[{"given":"Bruno","family":"Poirier","sequence":"first","affiliation":[{"name":"Cardio\u2010Vascular and metabolism Sanofi R&amp;D  Chilly Mazarin France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Pasquier","sequence":"additional","affiliation":[{"name":"Integrated Drug Discovery Sanofi R&amp;D  Chilly Mazarin 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