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Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure\u2013activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3<jats:italic>S<\/jats:italic>)\u20101\u2010[5\u2010<jats:italic>tert<\/jats:italic>\u2010butyl\u20103\u2010[(1\u2010cyclopropyltetrazol\u20105\u2010yl)methyl]triazolo[4,5\u2010<jats:italic>d<\/jats:italic>]pyrimidin\u20107\u2010yl]pyrrolidin\u20103\u2010ol (<jats:bold>39<\/jats:bold>), was tested in a kidney ischemia\u2013reperfusion model, in which it showed efficacy at a dose of 10\u2005mg\u2009kg<jats:sup>\u22121<\/jats:sup> (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound <jats:bold>39<\/jats:bold> was also protective in a model of renal fibrosis. Oral treatment with <jats:bold>39<\/jats:bold> at 3\u2005mg\u2009kg<jats:sup>\u22121<\/jats:sup> per day significantly decreased the amount of fibrosis by \u223c40\u2009% which was induced by unilateral ureter obstruction.<\/jats:p>","DOI":"10.1002\/cmdc.201500218","type":"journal-article","created":{"date-parts":[[2015,7,24]],"date-time":"2015-07-24T15:31:00Z","timestamp":1437751860000},"page":"179-189","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Novel Triazolopyrimidine\u2010Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases"],"prefix":"10.1002","volume":"11","author":[{"given":"Matthias","family":"Nettekoven","sequence":"first","affiliation":[{"name":"Roche Pharmaceutical Research and Early Development Small-Molecule Research Roche Innovation Center Basel  Grenzacher Str. 124 4070 Basel 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