Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase
Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2020-06, Vol.11 (6), p.1228-1235 |
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| creator | Andryianau, Gleb Kowalski, Michal Piotrowicz, Michal C. Rajkiewicz, Adam A. Dymek, Barbara Sklepkiewicz, Piotr L. Pluta, Elzbieta Stefaniak, Filip Czestkowski, Wojciech Olejniczak, Sylwia Mazur, Marzena Niedziejko, Piotr Koralewski, Robert Matyszewski, Krzysztof Gruza, Mariusz Zagozdzon, Agnieszka Salamon, Magdalena Rymaszewska, Aleksandra Welzer, Mikolaj Dzwonek, Karolina Golab, Jakub Olczak, Jacek Bartoszewicz, Agnieszka Golebiowski, Adam |
| description | Human
acidic mammalian chitinase (hAMCase) is one of two true chitinases
in humans, the function of which remains elusive. In addition to the
defense against highly antigenic chitin and chitin-containing pathogens
in the gastric and intestinal contents, AMCase has been implicated
in asthma, allergic inflammation, and ocular pathologies. Potent and
selective small-molecule inhibitors of this enzyme have not been identified
to date. Here we describe structural modifications of compound
OAT-177
, a previously developed inhibitor of mouse AMCase,
leading to
OAT-1441
, which displays high activity and
selectivity toward hAMCase. Significantly reduced off-target activity
toward the human ether-à-go-go-related gene (hERG) and a good
pharmacokinetic profile make
OAT-1441
a potential candidate
for further preclinical development as well as a useful tool compound
to study the physiological role of hAMCase. |
| doi_str_mv | 10.1021/acsmedchemlett.0c00092 |
| format | Article |
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acidic mammalian chitinase (hAMCase) is one of two true chitinases
in humans, the function of which remains elusive. In addition to the
defense against highly antigenic chitin and chitin-containing pathogens
in the gastric and intestinal contents, AMCase has been implicated
in asthma, allergic inflammation, and ocular pathologies. Potent and
selective small-molecule inhibitors of this enzyme have not been identified
to date. Here we describe structural modifications of compound
OAT-177
, a previously developed inhibitor of mouse AMCase,
leading to
OAT-1441
, which displays high activity and
selectivity toward hAMCase. Significantly reduced off-target activity
toward the human ether-à-go-go-related gene (hERG) and a good
pharmacokinetic profile make
OAT-1441
a potential candidate
for further preclinical development as well as a useful tool compound
to study the physiological role of hAMCase.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.0c00092</identifier><identifier>PMID: 32551005</identifier><language>eng</language><publisher>American Chemical Society</publisher><subject>Letter</subject><ispartof>ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1228-1235</ispartof><rights>Copyright © 2020 American Chemical Society 2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-22da11289415cf6cc1dbadb0a1df68f1bf439928dfa572eafc02f83b108259993</citedby><cites>FETCH-LOGICAL-c391t-22da11289415cf6cc1dbadb0a1df68f1bf439928dfa572eafc02f83b108259993</cites><orcidid>0000-0001-9932-2373 ; 0000-0002-1534-2690 ; 0000-0001-5960-2995 ; 0000-0001-7214-858X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294726/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294726/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,2763,27923,27924,53790,53792</link.rule.ids></links><search><creatorcontrib>Andryianau, Gleb</creatorcontrib><creatorcontrib>Kowalski, Michal</creatorcontrib><creatorcontrib>Piotrowicz, Michal C.</creatorcontrib><creatorcontrib>Rajkiewicz, Adam A.</creatorcontrib><creatorcontrib>Dymek, Barbara</creatorcontrib><creatorcontrib>Sklepkiewicz, Piotr L.</creatorcontrib><creatorcontrib>Pluta, Elzbieta</creatorcontrib><creatorcontrib>Stefaniak, Filip</creatorcontrib><creatorcontrib>Czestkowski, Wojciech</creatorcontrib><creatorcontrib>Olejniczak, Sylwia</creatorcontrib><creatorcontrib>Mazur, Marzena</creatorcontrib><creatorcontrib>Niedziejko, Piotr</creatorcontrib><creatorcontrib>Koralewski, Robert</creatorcontrib><creatorcontrib>Matyszewski, Krzysztof</creatorcontrib><creatorcontrib>Gruza, Mariusz</creatorcontrib><creatorcontrib>Zagozdzon, Agnieszka</creatorcontrib><creatorcontrib>Salamon, Magdalena</creatorcontrib><creatorcontrib>Rymaszewska, Aleksandra</creatorcontrib><creatorcontrib>Welzer, Mikolaj</creatorcontrib><creatorcontrib>Dzwonek, Karolina</creatorcontrib><creatorcontrib>Golab, Jakub</creatorcontrib><creatorcontrib>Olczak, Jacek</creatorcontrib><creatorcontrib>Bartoszewicz, Agnieszka</creatorcontrib><creatorcontrib>Golebiowski, Adam</creatorcontrib><title>Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase</title><title>ACS medicinal chemistry letters</title><description>Human
acidic mammalian chitinase (hAMCase) is one of two true chitinases
in humans, the function of which remains elusive. In addition to the
defense against highly antigenic chitin and chitin-containing pathogens
in the gastric and intestinal contents, AMCase has been implicated
in asthma, allergic inflammation, and ocular pathologies. Potent and
selective small-molecule inhibitors of this enzyme have not been identified
to date. Here we describe structural modifications of compound
OAT-177
, a previously developed inhibitor of mouse AMCase,
leading to
OAT-1441
, which displays high activity and
selectivity toward hAMCase. Significantly reduced off-target activity
toward the human ether-à-go-go-related gene (hERG) and a good
pharmacokinetic profile make
OAT-1441
a potential candidate
for further preclinical development as well as a useful tool compound
to study the physiological role of hAMCase.</description><subject>Letter</subject><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVUctOwzAQtBCIR-EXUI4cCKydpy9IUJ5SUQ_A2do4a2rkxCVOK-jXk4oK0dOOdkezoxnGTjlccBD8EnVoqNYzahz1_QVoAJBihx1ymZZxVhbZ7j98wI5C-ADIZVHAPjtIRJZxgOyQVTfUrvwXrmhuW4pvqbNLqqMXcqT7AZ5H0w6d-45urMclWoeVo-ipndnK9r6LvIkeFw220bW2tdXRMzYNOjssxjPb2xYDHbM9gy7QyWaO2Nv93ev4MZ5MH57G15NYJ5L3sRA1ci5KmfJMm1xrXldYV4C8NnlpeGXSREpR1gazQhAaDcKUScWhFJmUMhmxq1_d-aJaZ0NtP1hX88422H0rj1ZtX1o7U-9-qQoh00Lkg8DZRqDznwsKvWps0OQctuQXQYnBmZCQghio-S9Vdz6EjszfGw5qXZDaLkhtCkp-ACgJie0</recordid><startdate>20200611</startdate><enddate>20200611</enddate><creator>Andryianau, Gleb</creator><creator>Kowalski, Michal</creator><creator>Piotrowicz, Michal C.</creator><creator>Rajkiewicz, Adam A.</creator><creator>Dymek, Barbara</creator><creator>Sklepkiewicz, Piotr L.</creator><creator>Pluta, Elzbieta</creator><creator>Stefaniak, Filip</creator><creator>Czestkowski, Wojciech</creator><creator>Olejniczak, Sylwia</creator><creator>Mazur, Marzena</creator><creator>Niedziejko, Piotr</creator><creator>Koralewski, Robert</creator><creator>Matyszewski, Krzysztof</creator><creator>Gruza, Mariusz</creator><creator>Zagozdzon, Agnieszka</creator><creator>Salamon, Magdalena</creator><creator>Rymaszewska, Aleksandra</creator><creator>Welzer, Mikolaj</creator><creator>Dzwonek, Karolina</creator><creator>Golab, Jakub</creator><creator>Olczak, Jacek</creator><creator>Bartoszewicz, Agnieszka</creator><creator>Golebiowski, Adam</creator><general>American Chemical Society</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9932-2373</orcidid><orcidid>https://orcid.org/0000-0002-1534-2690</orcidid><orcidid>https://orcid.org/0000-0001-5960-2995</orcidid><orcidid>https://orcid.org/0000-0001-7214-858X</orcidid></search><sort><creationdate>20200611</creationdate><title>Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase</title><author>Andryianau, Gleb ; 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acidic mammalian chitinase (hAMCase) is one of two true chitinases
in humans, the function of which remains elusive. In addition to the
defense against highly antigenic chitin and chitin-containing pathogens
in the gastric and intestinal contents, AMCase has been implicated
in asthma, allergic inflammation, and ocular pathologies. Potent and
selective small-molecule inhibitors of this enzyme have not been identified
to date. Here we describe structural modifications of compound
OAT-177
, a previously developed inhibitor of mouse AMCase,
leading to
OAT-1441
, which displays high activity and
selectivity toward hAMCase. Significantly reduced off-target activity
toward the human ether-à-go-go-related gene (hERG) and a good
pharmacokinetic profile make
OAT-1441
a potential candidate
for further preclinical development as well as a useful tool compound
to study the physiological role of hAMCase.</abstract><pub>American Chemical Society</pub><pmid>32551005</pmid><doi>10.1021/acsmedchemlett.0c00092</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9932-2373</orcidid><orcidid>https://orcid.org/0000-0002-1534-2690</orcidid><orcidid>https://orcid.org/0000-0001-5960-2995</orcidid><orcidid>https://orcid.org/0000-0001-7214-858X</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | ACS Publications; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Letter |
| title | Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase |
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