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The RGD (Arg\u2010Gly\u2010Asp) integrin \u03b1v\u03b21 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non\u2010RGD hit small\u2010molecule \u03b1v\u03b21 inhibitors. We show that \u03b1v\u03b21 activity is embedded in a range of published \u03b14\u03b21 (VLA\u20104) ligands; we also demonstrate how a non\u2010RGD integrin inhibitor (of \u03b14\u03b21 in this case) was converted into a potent non\u2010zwitterionic RGD integrin inhibitor (of \u03b1v\u03b21 in this case). We designed urea ligands with excellent selectivity over \u03b14\u03b21 and the other \u03b1v integrins (\u03b1v\u03b23, \u03b1v\u03b25, \u03b1v\u03b26, \u03b1v\u03b28). In\u2005silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.<\/jats:p>","DOI":"10.1002\/cmdc.201900359","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T14:07:46Z","timestamp":1560780466000},"page":"1315-1320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Design of Potent, Selective and Drug\u2010Like RGD \u03b1v\u03b21 Small\u2010Molecule Inhibitors Derived from non\u2010RGD \u03b14\u03b21 Antagonists"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-2511","authenticated-orcid":false,"given":"Richard J. 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