Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD
Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds adminis...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-06, Vol.57 (11), p.4661-4676 |
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| container_end_page | 4676 |
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| container_issue | 11 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | De Savi, Chris Cox, Rhona J Warner, Daniel J Cook, Anthony R Dickinson, Mark R McDonough, Amy Morrill, Louis C Parker, Beth Andrews, Glen Young, Simon S Gilmour, Peter S Riley, Rob Dearman, Matthew S |
| description | Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential. |
| doi_str_mv | 10.1021/jm5001216 |
| format | Article |
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However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm5001216</identifier><identifier>PMID: 24785301</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Inhalation ; Animals ; Anti-Inflammatory Agents - adverse effects ; Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - pharmacology ; Benzamides - adverse effects ; Benzamides - chemical synthesis ; Benzamides - pharmacology ; Dogs ; Ferrets ; Humans ; Lipopolysaccharides - pharmacology ; Lung - drug effects ; Lung - immunology ; Lung - pathology ; Neutrophils - pathology ; Niacinamide - adverse effects ; Niacinamide - analogs & derivatives ; Niacinamide - chemical synthesis ; Niacinamide - pharmacology ; Phosphodiesterase 4 Inhibitors - adverse effects ; Phosphodiesterase 4 Inhibitors - chemical synthesis ; Phosphodiesterase 4 Inhibitors - pharmacology ; Pulmonary Disease, Chronic Obstructive - drug therapy ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Thiazoles - adverse effects ; Thiazoles - chemical synthesis ; Thiazoles - pharmacology ; Vomiting - chemically induced</subject><ispartof>Journal of medicinal chemistry, 2014-06, Vol.57 (11), p.4661-4676</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-3ec5a122f84e41d9a9283c70fe25c38e9994c8d3950ddafa970d17708dcea63e3</citedby><cites>FETCH-LOGICAL-a315t-3ec5a122f84e41d9a9283c70fe25c38e9994c8d3950ddafa970d17708dcea63e3</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/jm5001216$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm5001216$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24785301$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Savi, Chris</creatorcontrib><creatorcontrib>Cox, Rhona J</creatorcontrib><creatorcontrib>Warner, Daniel J</creatorcontrib><creatorcontrib>Cook, Anthony R</creatorcontrib><creatorcontrib>Dickinson, Mark R</creatorcontrib><creatorcontrib>McDonough, Amy</creatorcontrib><creatorcontrib>Morrill, Louis C</creatorcontrib><creatorcontrib>Parker, Beth</creatorcontrib><creatorcontrib>Andrews, Glen</creatorcontrib><creatorcontrib>Young, Simon S</creatorcontrib><creatorcontrib>Gilmour, Peter S</creatorcontrib><creatorcontrib>Riley, Rob</creatorcontrib><creatorcontrib>Dearman, Matthew S</creatorcontrib><title>Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.</description><subject>Administration, Inhalation</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - adverse effects</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Benzamides - adverse effects</subject><subject>Benzamides - chemical synthesis</subject><subject>Benzamides - pharmacology</subject><subject>Dogs</subject><subject>Ferrets</subject><subject>Humans</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Lung - drug effects</subject><subject>Lung - immunology</subject><subject>Lung - pathology</subject><subject>Neutrophils - pathology</subject><subject>Niacinamide - adverse effects</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - chemical synthesis</subject><subject>Niacinamide - pharmacology</subject><subject>Phosphodiesterase 4 Inhibitors - adverse effects</subject><subject>Phosphodiesterase 4 Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase 4 Inhibitors - pharmacology</subject><subject>Pulmonary Disease, Chronic Obstructive - drug therapy</subject><subject>Rats</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - adverse effects</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacology</subject><subject>Vomiting - chemically induced</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtPwzAQhC0EgvI48AeQL0hwCKztOI8jastDqkQPcI6MvaaukhhsR4h_T0qBE6fd1Xw70gwhpwyuGHB2ve4kAOOs2CETJjlkeQX5LpkAcJ7xgosDchjjGgAE42KfHPC8rKQANiFxbq3TSjs_RPrQr1SLhi5n83xzuBeXfIj0w6UVXfgPOu8wOU2XPmGfnGqp6s0o9K90NgSVnO-pt_RGf2_WB5pWSJ8CqtSNDxtt-ricHZM9q9qIJz_ziDzfzp-m99ni8e5herPIlGAyZQK1VIxzW-WYM1OrmldCl2CRSy0qrOs615URtQRjlFV1CYaVJVRGoyoEiiNysfV9C_59wJiazkWNbat6HOM2TApZ8KJi9YheblEdfIwBbfMWXKfCZ8Og2XTc_HU8smc_tsNLh-aP_C11BM63gNKxWfsh9GPKf4y-ANyZgUU</recordid><startdate>20140612</startdate><enddate>20140612</enddate><creator>De Savi, Chris</creator><creator>Cox, Rhona J</creator><creator>Warner, Daniel J</creator><creator>Cook, Anthony R</creator><creator>Dickinson, Mark R</creator><creator>McDonough, Amy</creator><creator>Morrill, Louis C</creator><creator>Parker, Beth</creator><creator>Andrews, Glen</creator><creator>Young, Simon S</creator><creator>Gilmour, Peter S</creator><creator>Riley, Rob</creator><creator>Dearman, Matthew S</creator><general>American Chemical Society</general><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>20140612</creationdate><title>Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD</title><author>De Savi, Chris ; Cox, Rhona J ; Warner, Daniel J ; Cook, Anthony R ; Dickinson, Mark R ; McDonough, Amy ; Morrill, Louis C ; Parker, Beth ; Andrews, Glen ; Young, Simon S ; Gilmour, Peter S ; Riley, Rob ; Dearman, Matthew S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-3ec5a122f84e41d9a9283c70fe25c38e9994c8d3950ddafa970d17708dcea63e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Administration, Inhalation</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - adverse effects</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Benzamides - adverse effects</topic><topic>Benzamides - chemical synthesis</topic><topic>Benzamides - pharmacology</topic><topic>Dogs</topic><topic>Ferrets</topic><topic>Humans</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Lung - drug effects</topic><topic>Lung - immunology</topic><topic>Lung - pathology</topic><topic>Neutrophils - pathology</topic><topic>Niacinamide - adverse effects</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - chemical synthesis</topic><topic>Niacinamide - pharmacology</topic><topic>Phosphodiesterase 4 Inhibitors - adverse effects</topic><topic>Phosphodiesterase 4 Inhibitors - chemical synthesis</topic><topic>Phosphodiesterase 4 Inhibitors - pharmacology</topic><topic>Pulmonary Disease, Chronic Obstructive - drug therapy</topic><topic>Rats</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - adverse effects</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - pharmacology</topic><topic>Vomiting - chemically induced</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Savi, Chris</creatorcontrib><creatorcontrib>Cox, Rhona J</creatorcontrib><creatorcontrib>Warner, Daniel J</creatorcontrib><creatorcontrib>Cook, Anthony R</creatorcontrib><creatorcontrib>Dickinson, Mark R</creatorcontrib><creatorcontrib>McDonough, Amy</creatorcontrib><creatorcontrib>Morrill, Louis C</creatorcontrib><creatorcontrib>Parker, Beth</creatorcontrib><creatorcontrib>Andrews, Glen</creatorcontrib><creatorcontrib>Young, Simon S</creatorcontrib><creatorcontrib>Gilmour, Peter S</creatorcontrib><creatorcontrib>Riley, Rob</creatorcontrib><creatorcontrib>Dearman, Matthew S</creatorcontrib><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>De Savi, Chris</au><au>Cox, Rhona J</au><au>Warner, Daniel J</au><au>Cook, Anthony R</au><au>Dickinson, Mark R</au><au>McDonough, Amy</au><au>Morrill, Louis C</au><au>Parker, Beth</au><au>Andrews, Glen</au><au>Young, Simon S</au><au>Gilmour, Peter S</au><au>Riley, Rob</au><au>Dearman, Matthew S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-06-12</date><risdate>2014</risdate><volume>57</volume><issue>11</issue><spage>4661</spage><epage>4676</epage><pages>4661-4676</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24785301</pmid><doi>10.1021/jm5001216</doi><tpages>16</tpages></addata></record> |
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| subjects | Administration, Inhalation Animals Anti-Inflammatory Agents - adverse effects Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - pharmacology Benzamides - adverse effects Benzamides - chemical synthesis Benzamides - pharmacology Dogs Ferrets Humans Lipopolysaccharides - pharmacology Lung - drug effects Lung - immunology Lung - pathology Neutrophils - pathology Niacinamide - adverse effects Niacinamide - analogs & derivatives Niacinamide - chemical synthesis Niacinamide - pharmacology Phosphodiesterase 4 Inhibitors - adverse effects Phosphodiesterase 4 Inhibitors - chemical synthesis Phosphodiesterase 4 Inhibitors - pharmacology Pulmonary Disease, Chronic Obstructive - drug therapy Rats Stereoisomerism Structure-Activity Relationship Thiazoles - adverse effects Thiazoles - chemical synthesis Thiazoles - pharmacology Vomiting - chemically induced |
| title | Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD |
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