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Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease\u2013anti\u2010protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead\u2010structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY\u2010678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced\u2010fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY\u200585\u20108501 ((4<jats:italic>S<\/jats:italic>)\u20104\u2010[4\u2010cyano\u20102\u2010(methylsulfonyl)phenyl]\u20103,6\u2010dimethyl\u20102\u2010oxo\u20101\u2010[3\u2010(trifluoromethyl)phenyl]\u20101,2,3,4\u2010tetrahydropyrimidine\u20105\u2010carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY\u200585\u20108501 is currently being tested in clinical studies for the treatment of pulmonary diseases.<\/jats:p>","DOI":"10.1002\/cmdc.201500131","type":"journal-article","created":{"date-parts":[[2015,6,17]],"date-time":"2015-06-17T11:00:12Z","timestamp":1434538812000},"page":"1163-1173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY\u200585\u20108501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases"],"prefix":"10.1002","volume":"10","author":[{"given":"Franz","family":"von\u2005Nussbaum","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volkhart M.\u2010J.","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swen","family":"Allerheiligen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Anlauf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"B\u00e4rfacker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Bechem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Delbeck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary F.","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Gerisch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Gielen\u2010Haertwig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmut","family":"Haning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"Karthaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Lang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klemens","family":"Lustig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Meibom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Mittendorf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Rosentreter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Sch\u00e4fer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Sch\u00e4fer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Schamberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leila A.","family":"Telan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Tersteegen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,6,17]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1124\/pr.110.002733","volume":"62","author":"Korkmaz B.","year":"2010","journal-title":"Pharmacol. 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