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Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases
Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respir...
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| Published in: | ChemMedChem 2015-07, Vol.10 (7), p.1163-1173 |
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| creator | von Nussbaum, Franz Li, Volkhart M.-J. Allerheiligen, Swen Anlauf, Sonja Bärfacker, Lars Bechem, Martin Delbeck, Martina Fitzgerald, Mary F. Gerisch, Michael Gielen-Haertwig, Heike Haning, Helmut Karthaus, Dagmar Lang, Dieter Lustig, Klemens Meibom, Daniel Mittendorf, Joachim Rosentreter, Ulrich Schäfer, Martina Schäfer, Stefan Schamberger, Jens Telan, Leila A. Tersteegen, Adrian |
| description | Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. 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–anti‐protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead‐structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY‐678. 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‐fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85‐8501 ((4S)‐4‐[4‐cyano‐2‐(methylsulfonyl)phenyl]‐3,6‐dimethyl‐2‐oxo‐1‐[3‐(trifluoromethyl)phenyl]‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85‐8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
Breathe better: It′s as potent as a low‐molecular‐weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85‐8501, a small‐molecule inhibitor with picomolar in vitro potency against HNE. BAY 85‐8501 is currently being assessed in clinical studies for pulmonary diseases. |
| doi_str_mv | 10.1002/cmdc.201500131 |
| format | article |
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Breathe better: It′s as potent as a low‐molecular‐weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85‐8501, a small‐molecule inhibitor with picomolar in vitro potency against HNE. BAY 85‐8501 is currently being assessed in clinical studies for pulmonary diseases.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201500131</identifier><identifier>PMID: 26083237</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>biginelli reaction ; biological activity ; Dose-Response Relationship, Drug ; elastase inhibitors ; Freezing ; Humans ; Leukocyte Elastase - antagonists & inhibitors ; Leukocyte Elastase - metabolism ; Lung Diseases - enzymology ; Molecular Conformation ; proteases ; Proteinase Inhibitory Proteins, Secretory - chemistry ; Proteinase Inhibitory Proteins, Secretory - pharmacology ; pyrimidinones ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacology ; Structure-Activity Relationship ; Sulfones - chemistry ; Sulfones - pharmacology</subject><ispartof>ChemMedChem, 2015-07, Vol.10 (7), p.1163-1173</ispartof><rights>2015 The Authors. Published by Wiley‐VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.</rights><rights>2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</rights><rights>2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3231-ce6d8ff7b9745fa1336ccdbafb4fa7781a0130d04ff14b2ff19a66ca5748f45d3</citedby><cites>FETCH-LOGICAL-c3231-ce6d8ff7b9745fa1336ccdbafb4fa7781a0130d04ff14b2ff19a66ca5748f45d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201500131$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201500131$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,786,790,891,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26083237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>von Nussbaum, Franz</creatorcontrib><creatorcontrib>Li, Volkhart M.-J.</creatorcontrib><creatorcontrib>Allerheiligen, Swen</creatorcontrib><creatorcontrib>Anlauf, Sonja</creatorcontrib><creatorcontrib>Bärfacker, Lars</creatorcontrib><creatorcontrib>Bechem, Martin</creatorcontrib><creatorcontrib>Delbeck, Martina</creatorcontrib><creatorcontrib>Fitzgerald, Mary F.</creatorcontrib><creatorcontrib>Gerisch, Michael</creatorcontrib><creatorcontrib>Gielen-Haertwig, Heike</creatorcontrib><creatorcontrib>Haning, Helmut</creatorcontrib><creatorcontrib>Karthaus, Dagmar</creatorcontrib><creatorcontrib>Lang, Dieter</creatorcontrib><creatorcontrib>Lustig, Klemens</creatorcontrib><creatorcontrib>Meibom, Daniel</creatorcontrib><creatorcontrib>Mittendorf, Joachim</creatorcontrib><creatorcontrib>Rosentreter, Ulrich</creatorcontrib><creatorcontrib>Schäfer, Martina</creatorcontrib><creatorcontrib>Schäfer, Stefan</creatorcontrib><creatorcontrib>Schamberger, Jens</creatorcontrib><creatorcontrib>Telan, Leila A.</creatorcontrib><creatorcontrib>Tersteegen, Adrian</creatorcontrib><title>Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. 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–anti‐protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead‐structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY‐678. 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‐fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85‐8501 ((4S)‐4‐[4‐cyano‐2‐(methylsulfonyl)phenyl]‐3,6‐dimethyl‐2‐oxo‐1‐[3‐(trifluoromethyl)phenyl]‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85‐8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
Breathe better: It′s as potent as a low‐molecular‐weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85‐8501, a small‐molecule inhibitor with picomolar in vitro potency against HNE. BAY 85‐8501 is currently being assessed in clinical studies for pulmonary diseases.</description><subject>biginelli reaction</subject><subject>biological activity</subject><subject>Dose-Response Relationship, Drug</subject><subject>elastase inhibitors</subject><subject>Freezing</subject><subject>Humans</subject><subject>Leukocyte Elastase - antagonists & inhibitors</subject><subject>Leukocyte Elastase - metabolism</subject><subject>Lung Diseases - enzymology</subject><subject>Molecular Conformation</subject><subject>proteases</subject><subject>Proteinase Inhibitory Proteins, Secretory - chemistry</subject><subject>Proteinase Inhibitory Proteins, Secretory - pharmacology</subject><subject>pyrimidinones</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Sulfones - chemistry</subject><subject>Sulfones - pharmacology</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNqFkUFv0zAYhiMEYmNw5Yj8A0ixEyd2OSCt6dpVKluldZo4WY5jr4bErmx3UE5c9nv2n_gluAqLxomLbX1-n_f77DdJ3iI4QhBmH0TXiFEGUQEhytGz5BjREqYEUfJ8OJPxUfLK-68QYkwRfZkcZSWkeZaT4-Rh5qT8qc0tCBsJJtpyEfSdBJU1yrqOB20NCBZMrPUBrGyQRuw_gnUULxppglZa9CKrwOT0y-9f97RIaQHRe8DBlWxl78dN09MBLMxG1zpYd0DOdx034ELugrPbjW7BWct94F6C2B6sdm1nDXd7MNVexqp_nbxQvPXyzd_9JLmena2r83R5OV9Up8tUxHehVMiyoUqRekxwoTjK81KIpuaqxooTQhGP3wUbiJVCuM7iOuZlKXhBMFW4aPKT5FPvu93VnWxEHNzxlm2d7uI4zHLN_r0xesNu7R3DRcyC4mgw6g2Es947qQYWQXaIjh2iY0N0EXj3tOMgf8wqCsa94Ltu5f4_dqz6PK2emqc9q32QPwaWu2-sJDkp2M3FnE3X0_nqBs3YMv8Djca5tQ</recordid><startdate>201507</startdate><enddate>201507</enddate><creator>von Nussbaum, Franz</creator><creator>Li, Volkhart M.-J.</creator><creator>Allerheiligen, Swen</creator><creator>Anlauf, Sonja</creator><creator>Bärfacker, Lars</creator><creator>Bechem, Martin</creator><creator>Delbeck, Martina</creator><creator>Fitzgerald, Mary F.</creator><creator>Gerisch, Michael</creator><creator>Gielen-Haertwig, Heike</creator><creator>Haning, Helmut</creator><creator>Karthaus, Dagmar</creator><creator>Lang, Dieter</creator><creator>Lustig, Klemens</creator><creator>Meibom, Daniel</creator><creator>Mittendorf, Joachim</creator><creator>Rosentreter, Ulrich</creator><creator>Schäfer, Martina</creator><creator>Schäfer, Stefan</creator><creator>Schamberger, Jens</creator><creator>Telan, Leila A.</creator><creator>Tersteegen, Adrian</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><scope>BSCLL</scope><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>201507</creationdate><title>Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases</title><author>von Nussbaum, Franz ; Li, Volkhart M.-J. ; Allerheiligen, Swen ; Anlauf, Sonja ; Bärfacker, Lars ; Bechem, Martin ; Delbeck, Martina ; Fitzgerald, Mary F. ; Gerisch, Michael ; Gielen-Haertwig, Heike ; Haning, Helmut ; Karthaus, Dagmar ; Lang, Dieter ; Lustig, Klemens ; Meibom, Daniel ; Mittendorf, Joachim ; Rosentreter, Ulrich ; Schäfer, Martina ; Schäfer, Stefan ; Schamberger, Jens ; Telan, Leila A. ; Tersteegen, Adrian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3231-ce6d8ff7b9745fa1336ccdbafb4fa7781a0130d04ff14b2ff19a66ca5748f45d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>biginelli reaction</topic><topic>biological activity</topic><topic>Dose-Response Relationship, Drug</topic><topic>elastase inhibitors</topic><topic>Freezing</topic><topic>Humans</topic><topic>Leukocyte Elastase - antagonists & inhibitors</topic><topic>Leukocyte Elastase - metabolism</topic><topic>Lung Diseases - enzymology</topic><topic>Molecular Conformation</topic><topic>proteases</topic><topic>Proteinase Inhibitory Proteins, Secretory - chemistry</topic><topic>Proteinase Inhibitory Proteins, Secretory - pharmacology</topic><topic>pyrimidinones</topic><topic>Pyrimidinones - chemistry</topic><topic>Pyrimidinones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Sulfones - chemistry</topic><topic>Sulfones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>von Nussbaum, Franz</creatorcontrib><creatorcontrib>Li, Volkhart M.-J.</creatorcontrib><creatorcontrib>Allerheiligen, Swen</creatorcontrib><creatorcontrib>Anlauf, Sonja</creatorcontrib><creatorcontrib>Bärfacker, Lars</creatorcontrib><creatorcontrib>Bechem, Martin</creatorcontrib><creatorcontrib>Delbeck, Martina</creatorcontrib><creatorcontrib>Fitzgerald, Mary F.</creatorcontrib><creatorcontrib>Gerisch, Michael</creatorcontrib><creatorcontrib>Gielen-Haertwig, Heike</creatorcontrib><creatorcontrib>Haning, Helmut</creatorcontrib><creatorcontrib>Karthaus, Dagmar</creatorcontrib><creatorcontrib>Lang, Dieter</creatorcontrib><creatorcontrib>Lustig, Klemens</creatorcontrib><creatorcontrib>Meibom, Daniel</creatorcontrib><creatorcontrib>Mittendorf, Joachim</creatorcontrib><creatorcontrib>Rosentreter, Ulrich</creatorcontrib><creatorcontrib>Schäfer, Martina</creatorcontrib><creatorcontrib>Schäfer, Stefan</creatorcontrib><creatorcontrib>Schamberger, Jens</creatorcontrib><creatorcontrib>Telan, Leila A.</creatorcontrib><creatorcontrib>Tersteegen, Adrian</creatorcontrib><collection>Istex</collection><collection>Open Access: Wiley-Blackwell Open Access Journals</collection><collection>Wiley Online Library</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>von Nussbaum, Franz</au><au>Li, Volkhart M.-J.</au><au>Allerheiligen, Swen</au><au>Anlauf, Sonja</au><au>Bärfacker, Lars</au><au>Bechem, Martin</au><au>Delbeck, Martina</au><au>Fitzgerald, Mary F.</au><au>Gerisch, Michael</au><au>Gielen-Haertwig, Heike</au><au>Haning, Helmut</au><au>Karthaus, Dagmar</au><au>Lang, Dieter</au><au>Lustig, Klemens</au><au>Meibom, Daniel</au><au>Mittendorf, Joachim</au><au>Rosentreter, Ulrich</au><au>Schäfer, Martina</au><au>Schäfer, Stefan</au><au>Schamberger, Jens</au><au>Telan, Leila A.</au><au>Tersteegen, Adrian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2015-07</date><risdate>2015</risdate><volume>10</volume><issue>7</issue><spage>1163</spage><epage>1173</epage><pages>1163-1173</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><notes>Funded Access</notes><notes>ark:/67375/WNG-DTDGPW1F-L</notes><notes>istex:EF49D1F87B6BC5AD1E7BB0325C193CA34BE7C1E0</notes><notes>ArticleID:CMDC201500131</notes><notes>Former affiliation and address during this project</notes><abstract>Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. 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–anti‐protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead‐structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY‐678. 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‐fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85‐8501 ((4S)‐4‐[4‐cyano‐2‐(methylsulfonyl)phenyl]‐3,6‐dimethyl‐2‐oxo‐1‐[3‐(trifluoromethyl)phenyl]‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85‐8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
Breathe better: It′s as potent as a low‐molecular‐weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85‐8501, a small‐molecule inhibitor with picomolar in vitro potency against HNE. BAY 85‐8501 is currently being assessed in clinical studies for pulmonary diseases.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>26083237</pmid><doi>10.1002/cmdc.201500131</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | biginelli reaction biological activity Dose-Response Relationship, Drug elastase inhibitors Freezing Humans Leukocyte Elastase - antagonists & inhibitors Leukocyte Elastase - metabolism Lung Diseases - enzymology Molecular Conformation proteases Proteinase Inhibitory Proteins, Secretory - chemistry Proteinase Inhibitory Proteins, Secretory - pharmacology pyrimidinones Pyrimidinones - chemistry Pyrimidinones - pharmacology Structure-Activity Relationship Sulfones - chemistry Sulfones - pharmacology |
| title | Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases |
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