Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bron...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-08, Vol.51 (16), p.4866-4869 |
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| container_end_page | 4869 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Jin, Jian Wang, Yonghui Shi, Dongchuan Wang, Feng Davis, Roderick S Jin, Qi Fu, Wei Foley, James J Webb, Edward F Dehaas, Chris J Berlanga, Manuela Burman, Miriam Sarau, Henry M Morrow, Dwight M Rao, Parvathi Kallal, Lorena A Moore, Michael L Rivero, Ralph A Palovich, Michael Salmon, Michael Belmonte, Kristen E Busch-Petersen, Jakob |
| description | High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders. |
| doi_str_mv | 10.1021/jm800634k |
| format | Article |
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Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800634k</identifier><identifier>PMID: 18680280</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Bronchoconstriction - drug effects ; Cholinergic system ; Drug Evaluation, Preclinical - methods ; Guinea Pigs ; Medical sciences ; Mice ; Muscarinic Antagonists - pharmacology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Phenylurea Compounds - pharmacology ; Quaternary Ammonium Compounds - pharmacology ; Rats ; Respiratory system ; Tyrosine - analogs & derivatives ; Tyrosine - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2008-08, Vol.51 (16), p.4866-4869</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-50bc86aba698e6ea8917daf767a327f33946c604a1b7074916bbe21a4b729baa3</citedby><cites>FETCH-LOGICAL-a381t-50bc86aba698e6ea8917daf767a327f33946c604a1b7074916bbe21a4b729baa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm800634k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm800634k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20598902$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18680280$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jin, Jian</creatorcontrib><creatorcontrib>Wang, Yonghui</creatorcontrib><creatorcontrib>Shi, Dongchuan</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Davis, Roderick S</creatorcontrib><creatorcontrib>Jin, Qi</creatorcontrib><creatorcontrib>Fu, Wei</creatorcontrib><creatorcontrib>Foley, James J</creatorcontrib><creatorcontrib>Webb, Edward F</creatorcontrib><creatorcontrib>Dehaas, Chris J</creatorcontrib><creatorcontrib>Berlanga, Manuela</creatorcontrib><creatorcontrib>Burman, Miriam</creatorcontrib><creatorcontrib>Sarau, Henry M</creatorcontrib><creatorcontrib>Morrow, Dwight M</creatorcontrib><creatorcontrib>Rao, Parvathi</creatorcontrib><creatorcontrib>Kallal, Lorena A</creatorcontrib><creatorcontrib>Moore, Michael L</creatorcontrib><creatorcontrib>Rivero, Ralph A</creatorcontrib><creatorcontrib>Palovich, Michael</creatorcontrib><creatorcontrib>Salmon, Michael</creatorcontrib><creatorcontrib>Belmonte, Kristen E</creatorcontrib><creatorcontrib>Busch-Petersen, Jakob</creatorcontrib><title>Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Bronchoconstriction - drug effects</subject><subject>Cholinergic system</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Guinea Pigs</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Muscarinic Antagonists - pharmacology</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Quaternary Ammonium Compounds - pharmacology</subject><subject>Rats</subject><subject>Respiratory system</subject><subject>Tyrosine - analogs & derivatives</subject><subject>Tyrosine - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1PGzEQhq2qVQkfh_6Bai9F4rBlbO_a3mMKFFBDiCA9W7OOl27Y2Km9WzX_HqNE4cJpRjOPXs08hHyh8J0Co-fLlQIQvHj-QEa0ZJAXCoqPZATAWM4E4wfkMMYlAHDK-GdyQJVQwBSMyOyyjcb_s2GT-Sabpq7L0C2yiXdP2dj0bSp3QzQYWteaNLH9pjN_fNc6mz1YY9e9D9nY9fjkXRv7eEw-NdhFe7KrR-T3z6v5xU0-ub--vRhPcuSK9nkJtVECaxSVssKiqqhcYCOFRM5kw3lVCCOgQFpLkEVFRV1bRrGoJatqRH5ETre56-D_Djb2epU-sV2HzvohapEChCx4As-2oAk-xmAbvQ7tCsNGU9Cv-vReX2K_7kKHemUXb-TOVwK-7QBMTromoDNt3HMMykpVwBKXb7mkxP7f7zE8ayG5LPV89qih_HF5N5Vz_estF03USz8El9y9c-ALfkKSLQ</recordid><startdate>20080828</startdate><enddate>20080828</enddate><creator>Jin, Jian</creator><creator>Wang, Yonghui</creator><creator>Shi, Dongchuan</creator><creator>Wang, Feng</creator><creator>Davis, Roderick S</creator><creator>Jin, Qi</creator><creator>Fu, Wei</creator><creator>Foley, James J</creator><creator>Webb, Edward F</creator><creator>Dehaas, Chris J</creator><creator>Berlanga, Manuela</creator><creator>Burman, Miriam</creator><creator>Sarau, Henry M</creator><creator>Morrow, Dwight M</creator><creator>Rao, Parvathi</creator><creator>Kallal, Lorena A</creator><creator>Moore, Michael L</creator><creator>Rivero, Ralph A</creator><creator>Palovich, Michael</creator><creator>Salmon, Michael</creator><creator>Belmonte, Kristen E</creator><creator>Busch-Petersen, Jakob</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</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>7X8</scope></search><sort><creationdate>20080828</creationdate><title>Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists</title><author>Jin, Jian ; Wang, Yonghui ; Shi, Dongchuan ; Wang, Feng ; Davis, Roderick S ; Jin, Qi ; Fu, Wei ; Foley, James J ; Webb, Edward F ; Dehaas, Chris J ; Berlanga, Manuela ; Burman, Miriam ; Sarau, Henry M ; Morrow, Dwight M ; Rao, Parvathi ; Kallal, Lorena A ; Moore, Michael L ; Rivero, Ralph A ; Palovich, Michael ; Salmon, Michael ; Belmonte, Kristen E ; Busch-Petersen, Jakob</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-50bc86aba698e6ea8917daf767a327f33946c604a1b7074916bbe21a4b729baa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Bronchoconstriction - drug effects</topic><topic>Cholinergic system</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Guinea Pigs</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Muscarinic Antagonists - pharmacology</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Quaternary Ammonium Compounds - pharmacology</topic><topic>Rats</topic><topic>Respiratory system</topic><topic>Tyrosine - analogs & derivatives</topic><topic>Tyrosine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jin, Jian</creatorcontrib><creatorcontrib>Wang, Yonghui</creatorcontrib><creatorcontrib>Shi, Dongchuan</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Davis, Roderick S</creatorcontrib><creatorcontrib>Jin, Qi</creatorcontrib><creatorcontrib>Fu, Wei</creatorcontrib><creatorcontrib>Foley, James J</creatorcontrib><creatorcontrib>Webb, Edward F</creatorcontrib><creatorcontrib>Dehaas, Chris J</creatorcontrib><creatorcontrib>Berlanga, Manuela</creatorcontrib><creatorcontrib>Burman, Miriam</creatorcontrib><creatorcontrib>Sarau, Henry M</creatorcontrib><creatorcontrib>Morrow, Dwight M</creatorcontrib><creatorcontrib>Rao, Parvathi</creatorcontrib><creatorcontrib>Kallal, Lorena A</creatorcontrib><creatorcontrib>Moore, Michael L</creatorcontrib><creatorcontrib>Rivero, Ralph A</creatorcontrib><creatorcontrib>Palovich, Michael</creatorcontrib><creatorcontrib>Salmon, Michael</creatorcontrib><creatorcontrib>Belmonte, Kristen E</creatorcontrib><creatorcontrib>Busch-Petersen, Jakob</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jin, Jian</au><au>Wang, Yonghui</au><au>Shi, Dongchuan</au><au>Wang, Feng</au><au>Davis, Roderick S</au><au>Jin, Qi</au><au>Fu, Wei</au><au>Foley, James J</au><au>Webb, Edward F</au><au>Dehaas, Chris J</au><au>Berlanga, Manuela</au><au>Burman, Miriam</au><au>Sarau, Henry M</au><au>Morrow, Dwight M</au><au>Rao, Parvathi</au><au>Kallal, Lorena A</au><au>Moore, Michael L</au><au>Rivero, Ralph A</au><au>Palovich, Michael</au><au>Salmon, Michael</au><au>Belmonte, Kristen E</au><au>Busch-Petersen, Jakob</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-08-28</date><risdate>2008</risdate><volume>51</volume><issue>16</issue><spage>4866</spage><epage>4869</epage><pages>4866-4869</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18680280</pmid><doi>10.1021/jm800634k</doi><tpages>4</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Bridged Bicyclo Compounds, Heterocyclic - pharmacology Bronchoconstriction - drug effects Cholinergic system Drug Evaluation, Preclinical - methods Guinea Pigs Medical sciences Mice Muscarinic Antagonists - pharmacology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Phenylurea Compounds - pharmacology Quaternary Ammonium Compounds - pharmacology Rats Respiratory system Tyrosine - analogs & derivatives Tyrosine - pharmacology |
| title | Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists |
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