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In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high\u2010throughput screening (HTS) campaign. The compound bound to MR with p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    =6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X\u2010ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced\u2010fit hypothesis that required movement of the Met852 side chain. An improvement in MR selectivity of 11\u2010 to 79\u2010fold over PR and 23\u2010 to 234\u2010fold over GR was obtained. Given the U\u2010shaped binding conformation, macrocyclizations were explored, yielding a macrocycle that bound to MR with p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    =7.3. Two protein\u2013ligand X\u2010ray structures were determined, confirming the hypothesized binding mode for the designed compounds.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.201600529","type":"journal-article","created":{"date-parts":[[2016,11,29]],"date-time":"2016-11-29T08:56:10Z","timestamp":1480409770000},"page":"50-65","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Structure\u2010Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-3836","authenticated-orcid":false,"given":"Anneli","family":"Nordqvist","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit AstraZeneca  Pepparedsleden\u20051 M\u00f6lndal 43183 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