Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metab...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2010-05, Vol.18 (10), p.3606-3617 |
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| creator | Mackman, Richard L. Ray, Adrian S. Hui, Hon C. Zhang, Lijun Birkus, Gabriel Boojamra, Constantine G. Desai, Manoj C. Douglas, Janet L. Gao, Ying Grant, Deborah Laflamme, Genevieve Lin, Kuei-Ying Markevitch, David Y. Mishra, Ruchika McDermott, Martin Pakdaman, Rowchanak Petrakovsky, Oleg V. Vela, Jennifer E. Cihlar, Tomas |
| description | GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid]
4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver
4 and its active phosphorylated metabolite
15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug
5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3
mg/kg) in Beagle dogs, high levels (>9.0
μM) of active metabolite
15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of
5 as a clinical candidate. |
| doi_str_mv | 10.1016/j.bmc.2010.03.041 |
| format | Article |
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4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver
4 and its active phosphorylated metabolite
15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug
5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3
mg/kg) in Beagle dogs, high levels (>9.0
μM) of active metabolite
15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of
5 as a clinical candidate.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2010.03.041</identifier><identifier>PMID: 20409721</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adenine - analogs & derivatives ; Adenine - chemical synthesis ; Adenine - pharmacology ; Animals ; Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Cathepsin A ; CD4-Positive T-Lymphocytes - drug effects ; Dogs ; Drug Design ; Drug Resistance, Viral - drug effects ; Drug Stability ; Guanosine - analogs & derivatives ; Guanosine - pharmacology ; HIV ; HIV-1 - drug effects ; Nucleosides ; Nucleosides - pharmacology ; Organophosphonates - pharmacology ; Phosphonates ; Prodrugs ; Prodrugs - metabolism ; Prodrugs - pharmacology ; Reverse transcriptase ; Reverse Transcriptase Inhibitors - chemical synthesis ; Reverse Transcriptase Inhibitors - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Bioorganic & medicinal chemistry, 2010-05, Vol.18 (10), p.3606-3617</ispartof><rights>2010 Elsevier Ltd</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-27bacb4990a1b99eba741495f09620e464dcbe4c01863c37e883b0c2fd481fd03</citedby><cites>FETCH-LOGICAL-c418t-27bacb4990a1b99eba741495f09620e464dcbe4c01863c37e883b0c2fd481fd03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089610002452$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20409721$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mackman, Richard L.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Hui, Hon C.</creatorcontrib><creatorcontrib>Zhang, Lijun</creatorcontrib><creatorcontrib>Birkus, Gabriel</creatorcontrib><creatorcontrib>Boojamra, Constantine G.</creatorcontrib><creatorcontrib>Desai, Manoj C.</creatorcontrib><creatorcontrib>Douglas, Janet L.</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Grant, Deborah</creatorcontrib><creatorcontrib>Laflamme, Genevieve</creatorcontrib><creatorcontrib>Lin, Kuei-Ying</creatorcontrib><creatorcontrib>Markevitch, David Y.</creatorcontrib><creatorcontrib>Mishra, Ruchika</creatorcontrib><creatorcontrib>McDermott, Martin</creatorcontrib><creatorcontrib>Pakdaman, Rowchanak</creatorcontrib><creatorcontrib>Petrakovsky, Oleg V.</creatorcontrib><creatorcontrib>Vela, Jennifer E.</creatorcontrib><creatorcontrib>Cihlar, Tomas</creatorcontrib><title>Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid]
4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver
4 and its active phosphorylated metabolite
15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug
5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3
mg/kg) in Beagle dogs, high levels (>9.0
μM) of active metabolite
15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of
5 as a clinical candidate.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - chemical synthesis</subject><subject>Adenine - pharmacology</subject><subject>Animals</subject><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Cathepsin A</subject><subject>CD4-Positive T-Lymphocytes - drug effects</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Drug Resistance, Viral - drug effects</subject><subject>Drug Stability</subject><subject>Guanosine - analogs & derivatives</subject><subject>Guanosine - pharmacology</subject><subject>HIV</subject><subject>HIV-1 - drug effects</subject><subject>Nucleosides</subject><subject>Nucleosides - pharmacology</subject><subject>Organophosphonates - pharmacology</subject><subject>Phosphonates</subject><subject>Prodrugs</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - pharmacology</subject><subject>Reverse transcriptase</subject><subject>Reverse Transcriptase Inhibitors - chemical synthesis</subject><subject>Reverse Transcriptase Inhibitors - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kdFuFCEUhonR2G31Abwx3GkTZz0MdGbQK9Nq26SJiVZvCQNnumxmYAtMk_VtfFOZbPXSCwKHfOeH8_-EvGKwZsCa99t1P5l1DaUGvgbBnpAVE42oOJfsKVmBbLoKOtkckeOUtgBQC8mek6MaBMi2Zivy-8IlEx4w7mkY6OX3SjLOPtALTO7Ov6Np7_OmnBPV3tKwy25yv3R2wS-4npzVGekuBhvnu7TcFZz6IjhSP5sRQ3K2AJuQyvILfHX9k0YsLyakOWqfTHS7rEv19tvtKXV-43qXQzx8RnQvyLNBjwlfPu4n5MeXz7fnV9XN18vr8083lRGsy1Xd9tr0QkrQrJcSe90KJuTZUEyoAYsr1vQoDLCu4Ya32HW8B1MPVnRssMBPyJuDbpnmfsaU1VSswXHUHsOcVMv5GUguZCHZgTQxpBRxULvoJh33ioFaglFbVYJRSzAKuCrBlJ7Xj-pzP6H91_E3iQJ8PABYZnxwGFUyDr1B6yKarGxw_5H_A0lbntw</recordid><startdate>20100515</startdate><enddate>20100515</enddate><creator>Mackman, Richard L.</creator><creator>Ray, Adrian S.</creator><creator>Hui, Hon C.</creator><creator>Zhang, Lijun</creator><creator>Birkus, Gabriel</creator><creator>Boojamra, Constantine G.</creator><creator>Desai, Manoj C.</creator><creator>Douglas, Janet L.</creator><creator>Gao, Ying</creator><creator>Grant, Deborah</creator><creator>Laflamme, Genevieve</creator><creator>Lin, Kuei-Ying</creator><creator>Markevitch, David Y.</creator><creator>Mishra, Ruchika</creator><creator>McDermott, Martin</creator><creator>Pakdaman, Rowchanak</creator><creator>Petrakovsky, Oleg V.</creator><creator>Vela, Jennifer E.</creator><creator>Cihlar, Tomas</creator><general>Elsevier Ltd</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>20100515</creationdate><title>Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148</title><author>Mackman, Richard L. ; Ray, Adrian S. ; Hui, Hon C. ; Zhang, Lijun ; Birkus, Gabriel ; Boojamra, Constantine G. ; Desai, Manoj C. ; Douglas, Janet L. ; Gao, Ying ; Grant, Deborah ; Laflamme, Genevieve ; Lin, Kuei-Ying ; Markevitch, David Y. ; Mishra, Ruchika ; McDermott, Martin ; Pakdaman, Rowchanak ; Petrakovsky, Oleg V. ; Vela, Jennifer E. ; Cihlar, Tomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-27bacb4990a1b99eba741495f09620e464dcbe4c01863c37e883b0c2fd481fd03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - chemical synthesis</topic><topic>Adenine - pharmacology</topic><topic>Animals</topic><topic>Anti-HIV Agents - chemical synthesis</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Cathepsin A</topic><topic>CD4-Positive T-Lymphocytes - drug effects</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Drug Resistance, Viral - drug effects</topic><topic>Drug Stability</topic><topic>Guanosine - analogs & derivatives</topic><topic>Guanosine - pharmacology</topic><topic>HIV</topic><topic>HIV-1 - drug effects</topic><topic>Nucleosides</topic><topic>Nucleosides - pharmacology</topic><topic>Organophosphonates - pharmacology</topic><topic>Phosphonates</topic><topic>Prodrugs</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - pharmacology</topic><topic>Reverse transcriptase</topic><topic>Reverse Transcriptase Inhibitors - chemical synthesis</topic><topic>Reverse Transcriptase Inhibitors - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mackman, Richard L.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Hui, Hon C.</creatorcontrib><creatorcontrib>Zhang, Lijun</creatorcontrib><creatorcontrib>Birkus, Gabriel</creatorcontrib><creatorcontrib>Boojamra, Constantine G.</creatorcontrib><creatorcontrib>Desai, Manoj C.</creatorcontrib><creatorcontrib>Douglas, Janet L.</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Grant, Deborah</creatorcontrib><creatorcontrib>Laflamme, Genevieve</creatorcontrib><creatorcontrib>Lin, Kuei-Ying</creatorcontrib><creatorcontrib>Markevitch, David Y.</creatorcontrib><creatorcontrib>Mishra, Ruchika</creatorcontrib><creatorcontrib>McDermott, Martin</creatorcontrib><creatorcontrib>Pakdaman, Rowchanak</creatorcontrib><creatorcontrib>Petrakovsky, Oleg V.</creatorcontrib><creatorcontrib>Vela, Jennifer E.</creatorcontrib><creatorcontrib>Cihlar, Tomas</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>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mackman, Richard L.</au><au>Ray, Adrian S.</au><au>Hui, Hon C.</au><au>Zhang, Lijun</au><au>Birkus, Gabriel</au><au>Boojamra, Constantine G.</au><au>Desai, Manoj C.</au><au>Douglas, Janet L.</au><au>Gao, Ying</au><au>Grant, Deborah</au><au>Laflamme, Genevieve</au><au>Lin, Kuei-Ying</au><au>Markevitch, David Y.</au><au>Mishra, Ruchika</au><au>McDermott, Martin</au><au>Pakdaman, Rowchanak</au><au>Petrakovsky, Oleg V.</au><au>Vela, Jennifer E.</au><au>Cihlar, Tomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2010-05-15</date><risdate>2010</risdate><volume>18</volume><issue>10</issue><spage>3606</spage><epage>3617</epage><pages>3606-3617</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid]
4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver
4 and its active phosphorylated metabolite
15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug
5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3
mg/kg) in Beagle dogs, high levels (>9.0
μM) of active metabolite
15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of
5 as a clinical candidate.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>20409721</pmid><doi>10.1016/j.bmc.2010.03.041</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2010-05, Vol.18 (10), p.3606-3617 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Adenine - analogs & derivatives Adenine - chemical synthesis Adenine - pharmacology Animals Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Cathepsin A CD4-Positive T-Lymphocytes - drug effects Dogs Drug Design Drug Resistance, Viral - drug effects Drug Stability Guanosine - analogs & derivatives Guanosine - pharmacology HIV HIV-1 - drug effects Nucleosides Nucleosides - pharmacology Organophosphonates - pharmacology Phosphonates Prodrugs Prodrugs - metabolism Prodrugs - pharmacology Reverse transcriptase Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - pharmacology Tumor Cells, Cultured |
| title | Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148 |
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