The in vivo efficacy and side effect pharmacology of GS‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β2‐adrenoceptor agonist in preclinical animal species
Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β2‐adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology...
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| Veröffentlicht in: | Pharmacology research & perspectives 2014-08, Vol.2 (4), p.n/a |
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| creator | Salmon, Michael Tannheimer, Stacey L. Gentzler, Terry T. Cui, Zhi‐Hua Sorensen, Eric A. Hartsough, Kimberly C. Kim, Musong Purvis, Lafe J. Barrett, Edward G. McDonald, Jacob D. Rudolph, Karin Doyle‐Eisele, Melanie Kuehl, Philip J. Royer, Christopher M. Baker, William R. Phillips, Gary B. Wright, Clifford D. |
| description | Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β2‐adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)‐6‐[[3‐[[4‐[5‐[[2‐Hydroxy‐2‐(8‐hydroxy‐2‐oxo‐1,2‐dihydroquinolin‐5‐yl)ethyl]amino]pent‐1‐ynyl]phenyl]carbamoyl]phenyl]sulfonyl]‐4‐[(3‐methoxyphenyl)amino]‐8‐methylquinoline‐3‐carboxamide (GS‐5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long‐acting β2‐adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS‐5759 dose‐dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS‐5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS‐5759 was dosed as a fine‐particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS‐induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS‐5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS‐5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti‐inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device.
e00046 |
| doi_str_mv | 10.1002/prp2.46 |
| format | Article |
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e00046</description><subject>Animal model</subject><subject>anti‐inflammatory</subject><subject>bronchodilator</subject><subject>COPD</subject><subject>Original</subject><subject>phoshphodiestersae 4</subject><subject>β2‐adrenoceptor agonist</subject><issn>2052-1707</issn><issn>2052-1707</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNpVkd9KHDEUxoNUVFT6Crm3u-b_zNwUirRaECp2ex2ymTOzkWwyJOOWvfMRfBbvfQUfok9ixi3FXoQvJznfLx85CH2kZE4JYedDGthcqD10xIhkM1qR6sO7_SE6zfmOEEKpIJSzA3TIpCRSNvIIPS9WgF3AG7eJGLrOWWO32IQWZ9fCdAJ2xMPKpLWx0cd-i2OHL3_-eXiUlWw-YYND3IDHS9fdBzu6GIwv_TGX1TrIIySTAYvyyMot3RjTG93H0BeGKY7Q45cnNhVtghAtDG9NfQwuj1O2IYH1LpRovnjdukgewBb4CdrvjM9w-leP0a9vXxcXV7PrH5ffL75cz3paN2qmAICzRkjeWdrwiilLaFszVdeWGguG8obIpSoKNWemskxxKqqa1OUTQfBj9HnHHe6Xa2gthDEZr4dUwqStjsbp_2-CW-k-brSgtRK8KoCzHeC387D9Z6RETxPU0wS1UPrm9oYJxV8BW-uVnQ</recordid><startdate>201408</startdate><enddate>201408</enddate><creator>Salmon, Michael</creator><creator>Tannheimer, Stacey L.</creator><creator>Gentzler, Terry T.</creator><creator>Cui, Zhi‐Hua</creator><creator>Sorensen, Eric A.</creator><creator>Hartsough, Kimberly C.</creator><creator>Kim, Musong</creator><creator>Purvis, Lafe J.</creator><creator>Barrett, Edward G.</creator><creator>McDonald, Jacob D.</creator><creator>Rudolph, Karin</creator><creator>Doyle‐Eisele, Melanie</creator><creator>Kuehl, Philip J.</creator><creator>Royer, Christopher M.</creator><creator>Baker, William R.</creator><creator>Phillips, Gary B.</creator><creator>Wright, Clifford D.</creator><general>Blackwell Publishing Ltd</general><scope>24P</scope><scope>5PM</scope></search><sort><creationdate>201408</creationdate><title>The in vivo efficacy and side effect pharmacology of GS‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β2‐adrenoceptor agonist in preclinical animal species</title><author>Salmon, Michael ; Tannheimer, Stacey L. ; Gentzler, Terry T. ; Cui, Zhi‐Hua ; Sorensen, Eric A. ; Hartsough, Kimberly C. ; Kim, Musong ; Purvis, Lafe J. ; Barrett, Edward G. ; McDonald, Jacob D. ; Rudolph, Karin ; Doyle‐Eisele, Melanie ; Kuehl, Philip J. ; Royer, Christopher M. ; Baker, William R. ; Phillips, Gary B. ; Wright, Clifford D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g1896-6eee329453fc193726c01d82688c1acea13905b6a13e832a7c263147808052e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animal model</topic><topic>anti‐inflammatory</topic><topic>bronchodilator</topic><topic>COPD</topic><topic>Original</topic><topic>phoshphodiestersae 4</topic><topic>β2‐adrenoceptor agonist</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salmon, Michael</creatorcontrib><creatorcontrib>Tannheimer, Stacey L.</creatorcontrib><creatorcontrib>Gentzler, Terry T.</creatorcontrib><creatorcontrib>Cui, Zhi‐Hua</creatorcontrib><creatorcontrib>Sorensen, Eric A.</creatorcontrib><creatorcontrib>Hartsough, Kimberly C.</creatorcontrib><creatorcontrib>Kim, Musong</creatorcontrib><creatorcontrib>Purvis, Lafe J.</creatorcontrib><creatorcontrib>Barrett, Edward G.</creatorcontrib><creatorcontrib>McDonald, Jacob D.</creatorcontrib><creatorcontrib>Rudolph, Karin</creatorcontrib><creatorcontrib>Doyle‐Eisele, Melanie</creatorcontrib><creatorcontrib>Kuehl, Philip J.</creatorcontrib><creatorcontrib>Royer, Christopher M.</creatorcontrib><creatorcontrib>Baker, William R.</creatorcontrib><creatorcontrib>Phillips, Gary B.</creatorcontrib><creatorcontrib>Wright, Clifford D.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pharmacology research & perspectives</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salmon, Michael</au><au>Tannheimer, Stacey L.</au><au>Gentzler, Terry T.</au><au>Cui, Zhi‐Hua</au><au>Sorensen, Eric A.</au><au>Hartsough, Kimberly C.</au><au>Kim, Musong</au><au>Purvis, Lafe J.</au><au>Barrett, Edward G.</au><au>McDonald, Jacob D.</au><au>Rudolph, Karin</au><au>Doyle‐Eisele, Melanie</au><au>Kuehl, Philip J.</au><au>Royer, Christopher M.</au><au>Baker, William R.</au><au>Phillips, Gary B.</au><au>Wright, Clifford D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The in vivo efficacy and side effect pharmacology of GS‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β2‐adrenoceptor agonist in preclinical animal species</atitle><jtitle>Pharmacology research & perspectives</jtitle><date>2014-08</date><risdate>2014</risdate><volume>2</volume><issue>4</issue><epage>n/a</epage><issn>2052-1707</issn><eissn>2052-1707</eissn><abstract>Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β2‐adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)‐6‐[[3‐[[4‐[5‐[[2‐Hydroxy‐2‐(8‐hydroxy‐2‐oxo‐1,2‐dihydroquinolin‐5‐yl)ethyl]amino]pent‐1‐ynyl]phenyl]carbamoyl]phenyl]sulfonyl]‐4‐[(3‐methoxyphenyl)amino]‐8‐methylquinoline‐3‐carboxamide (GS‐5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long‐acting β2‐adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS‐5759 dose‐dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS‐5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS‐5759 was dosed as a fine‐particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS‐induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS‐5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS‐5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti‐inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device.
e00046</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>25505595</pmid><doi>10.1002/prp2.46</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley-Blackwell Open Access Titles; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animal model anti‐inflammatory bronchodilator COPD Original phoshphodiestersae 4 β2‐adrenoceptor agonist |
| title | The in vivo efficacy and side effect pharmacology of GS‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β2‐adrenoceptor agonist in preclinical animal species |
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