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The recent approval of finerenone for diabetic kidney disease, along with expanding opportunities to treat chronic kidney disease and heart failure with preserved ejection fraction has led to a continued interest in MR antagonism. This article describes the identification and initial optimization of MR antagonists based on a phenylglycine scaffold containing an acylurea motif. Optimization efforts aimed at enhancing MR potency and DMPK properties revealed that replacing the phenylglycine scaffold with\n                    <jats:sc>l<\/jats:sc>\n                    \u2010alanine avoided a risk of racemization at the stereocenter. The most potent compound exhibited an MR binding affinity of p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    \u2009=\u20099.3 and a potency in human MR reporter gene assay of pIC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20098.4. X\u2010ray crystallography of a protein\u2013ligand complex structure with an\n                    <jats:sc>l<\/jats:sc>\n                    \u2010alanine based compound revealed an internal hydrogen bond imposing a cyclic conformation on the acylurea, which in turn formed a bidentate hydrogen bond interaction with the side chain of Asn770, a key polar interaction site in MR for endogenous as well as synthetic ligands. Further lead generation efforts identified two compounds with suitable in vivo PK properties allowing assessment of their effect on acute urinary electrolyte excretion.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501047","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T19:09:01Z","timestamp":1777576141000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mineralocorticoid Receptor Antagonists With an Acylurea as a Key Polar Interaction Motif"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-3836","authenticated-orcid":false,"given":"Anneli","family":"Nordqvist","sequence":"first","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Lindmark","sequence":"additional","affiliation":[{"name":"DMPK Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Granberg","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Aagaard","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Barlind","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Fredenwall","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hansson","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Hogner","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Ivarsson","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Johansson","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Pharmaron Beijing Co. 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