Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs
The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha 2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl es...
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| Veröffentlicht in: | International journal of pharmaceutics 2005-05, Vol.295 (1), p.121-127 |
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| creator | Niemi, Riku Huuskonen, Juhani Laine, Krista Järvinen, Tomi |
| description | The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha
2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37
°C;
t
1/2
=
310 days) and optimal lipophilicity (log
P
app
=
1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine. |
| doi_str_mv | 10.1016/j.ijpharm.2005.02.002 |
| format | Article |
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2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37
°C;
t
1/2
=
310 days) and optimal lipophilicity (log
P
app
=
1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine.</description><identifier>ISSN: 0378-5173</identifier><identifier>EISSN: 1873-3476</identifier><identifier>DOI: 10.1016/j.ijpharm.2005.02.002</identifier><identifier>PMID: 15847997</identifier><identifier>CODEN: IJPHDE</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Animals ; Biological and medical sciences ; General pharmacology ; Hydrolysis ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Indans - chemical synthesis ; Indans - chemistry ; Indans - pharmacology ; Intraocular pressure ; Intraocular Pressure - drug effects ; Medical sciences ; MPV-2426 ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. Drug treatments ; Physicochemical properties ; Prodrugs ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacology ; Rabbits ; Solubility ; Stability ; Synthesis</subject><ispartof>International journal of pharmaceutics, 2005-05, Vol.295 (1), p.121-127</ispartof><rights>2005 Elsevier B.V.</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-cb2abce776b9c7b7d2182b1b52933ec08e6a86dca6c106d719b6f5a1315fc91f3</citedby><cites>FETCH-LOGICAL-c393t-cb2abce776b9c7b7d2182b1b52933ec08e6a86dca6c106d719b6f5a1315fc91f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0378517305001080$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16737684$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15847997$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Niemi, Riku</creatorcontrib><creatorcontrib>Huuskonen, Juhani</creatorcontrib><creatorcontrib>Laine, Krista</creatorcontrib><creatorcontrib>Järvinen, Tomi</creatorcontrib><title>Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs</title><title>International journal of pharmaceutics</title><addtitle>Int J Pharm</addtitle><description>The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha
2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37
°C;
t
1/2
=
310 days) and optimal lipophilicity (log
P
app
=
1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>General pharmacology</subject><subject>Hydrolysis</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Indans - chemical synthesis</subject><subject>Indans - chemistry</subject><subject>Indans - pharmacology</subject><subject>Intraocular pressure</subject><subject>Intraocular Pressure - drug effects</subject><subject>Medical sciences</subject><subject>MPV-2426</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Physicochemical properties</subject><subject>Prodrugs</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Rabbits</subject><subject>Solubility</subject><subject>Stability</subject><subject>Synthesis</subject><issn>0378-5173</issn><issn>1873-3476</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtv1DAURi0EokPhJ7TKhq5I8GNiJytUVX0gVeqircTOcuzrjkdJPPgmVPPv8TCRumR17-J893EIOWO0YpTJ79sqbHcbk4aKU1pXlFeU8ndkxRolSrFW8j1ZUaGasmZKnJBPiFtKqeRMfCQnrG7Wqm3Vivx63I_TBjDgt2Kzdyn2-3-9GV0RximZaOfepGKXAHFOUPTxFVIYXwrwHuyERfSFNy72Q3BhhAxGl-YX_Ew-eNMjfFnqKXm-uX66uivvH25_Xl3el1a0Yiptx01nQSnZtVZ1ynHW8I51NW-FAEsbkKaRzhppGZVOsbaTvjZMsNrblnlxSi6Oc_Pi3zPgpIeAFvrejBBn1FKp_KlYZ7A-gjZFxARe71IYTNprRvVBqd7qRak-KNWU66w0586XBXM3gHtLLQ4z8HUBDFrT-2RGG_CNk0oo2RwO-HHkIOv4EyBptAFGCy6kbFK7GP5zyl8gj5l_</recordid><startdate>20050513</startdate><enddate>20050513</enddate><creator>Niemi, Riku</creator><creator>Huuskonen, Juhani</creator><creator>Laine, Krista</creator><creator>Järvinen, Tomi</creator><general>Elsevier B.V</general><general>Elsevier</general><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>20050513</creationdate><title>Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs</title><author>Niemi, Riku ; Huuskonen, Juhani ; Laine, Krista ; Järvinen, Tomi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-cb2abce776b9c7b7d2182b1b52933ec08e6a86dca6c106d719b6f5a1315fc91f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>General pharmacology</topic><topic>Hydrolysis</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Indans - chemical synthesis</topic><topic>Indans - chemistry</topic><topic>Indans - pharmacology</topic><topic>Intraocular pressure</topic><topic>Intraocular Pressure - drug effects</topic><topic>Medical sciences</topic><topic>MPV-2426</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Physicochemical properties</topic><topic>Prodrugs</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Rabbits</topic><topic>Solubility</topic><topic>Stability</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Niemi, Riku</creatorcontrib><creatorcontrib>Huuskonen, Juhani</creatorcontrib><creatorcontrib>Laine, Krista</creatorcontrib><creatorcontrib>Järvinen, Tomi</creatorcontrib><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>International journal of pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Niemi, Riku</au><au>Huuskonen, Juhani</au><au>Laine, Krista</au><au>Järvinen, Tomi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs</atitle><jtitle>International journal of pharmaceutics</jtitle><addtitle>Int J Pharm</addtitle><date>2005-05-13</date><risdate>2005</risdate><volume>295</volume><issue>1</issue><spage>121</spage><epage>127</epage><pages>121-127</pages><issn>0378-5173</issn><eissn>1873-3476</eissn><coden>IJPHDE</coden><abstract>The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha
2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37
°C;
t
1/2
=
310 days) and optimal lipophilicity (log
P
app
=
1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>15847997</pmid><doi>10.1016/j.ijpharm.2005.02.002</doi><tpages>7</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Biological and medical sciences General pharmacology Hydrolysis Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Indans - chemical synthesis Indans - chemistry Indans - pharmacology Intraocular pressure Intraocular Pressure - drug effects Medical sciences MPV-2426 Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Physicochemical properties Prodrugs Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Rabbits Solubility Stability Synthesis |
| title | Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs |
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