Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs
The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-d-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-d-glucamine) salt, 1...
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| Veröffentlicht in: | Journal of medicinal chemistry 2000-03, Vol.43 (6), p.1234-1241 |
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| creator | Hale, Jeffrey J Mills, Sander G MacCoss, Malcolm Dorn, Conrad P Finke, Paul E Budhu, Richard J Reamer, Robert A Huskey, Su-Er W Luffer-Atlas, Debra Dean, Brian J McGowan, Erin M Feeney, William P Chiu, Shuet-Hing Lee Cascieri, Margaret A Chicchi, Gary G Kurtz, Marc M Sadowski, Sharon Ber, Elzbieta Tattersall, F. David Rupniak, Nadia M. J Williams, Angela R Rycroft, Wayne Hargreaves, Richard Metzger, Joseph M MacIntyre, D. Euan |
| description | The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-d-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-d-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans. |
| doi_str_mv | 10.1021/jm990617v |
| format | Article |
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David ; Rupniak, Nadia M. J ; Williams, Angela R ; Rycroft, Wayne ; Hargreaves, Richard ; Metzger, Joseph M ; MacIntyre, D. Euan</creator><creatorcontrib>Hale, Jeffrey J ; Mills, Sander G ; MacCoss, Malcolm ; Dorn, Conrad P ; Finke, Paul E ; Budhu, Richard J ; Reamer, Robert A ; Huskey, Su-Er W ; Luffer-Atlas, Debra ; Dean, Brian J ; McGowan, Erin M ; Feeney, William P ; Chiu, Shuet-Hing Lee ; Cascieri, Margaret A ; Chicchi, Gary G ; Kurtz, Marc M ; Sadowski, Sharon ; Ber, Elzbieta ; Tattersall, F. David ; Rupniak, Nadia M. J ; Williams, Angela R ; Rycroft, Wayne ; Hargreaves, Richard ; Metzger, Joseph M ; MacIntyre, D. Euan</creatorcontrib><description>The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-d-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-d-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm990617v</identifier><identifier>PMID: 10737756</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acetals - chemical synthesis ; Acetals - chemistry ; Acetals - metabolism ; Acetals - pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - metabolism ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Antiemetics - chemical synthesis ; Antiemetics - chemistry ; Antiemetics - metabolism ; Antiemetics - pharmacology ; Antineoplastic Agents ; Aprepitant ; Biological and medical sciences ; Cisplatin ; Dogs ; Drug Evaluation, Preclinical ; Ferrets ; Guinea Pigs ; Humans ; Medical sciences ; Morpholines - chemical synthesis ; Morpholines - chemistry ; Morpholines - metabolism ; Morpholines - pharmacology ; Neurokinin-1 Receptor Antagonists ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - metabolism ; Prodrugs - pharmacology ; Rats ; Solubility ; Stereoisomerism ; Structure-Activity Relationship ; Vomiting - chemically induced ; Vomiting - drug therapy ; Water</subject><ispartof>Journal of medicinal chemistry, 2000-03, Vol.43 (6), p.1234-1241</ispartof><rights>Copyright © 2000 American Chemical Society</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-3f6651343494fbd1291bea97185935f6f9582f2d17e31dcd7ed7c42dd81af07e3</citedby><cites>FETCH-LOGICAL-a378t-3f6651343494fbd1291bea97185935f6f9582f2d17e31dcd7ed7c42dd81af07e3</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/jm990617v$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm990617v$$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=1328139$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10737756$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hale, Jeffrey J</creatorcontrib><creatorcontrib>Mills, Sander G</creatorcontrib><creatorcontrib>MacCoss, Malcolm</creatorcontrib><creatorcontrib>Dorn, Conrad P</creatorcontrib><creatorcontrib>Finke, Paul E</creatorcontrib><creatorcontrib>Budhu, Richard J</creatorcontrib><creatorcontrib>Reamer, Robert A</creatorcontrib><creatorcontrib>Huskey, Su-Er W</creatorcontrib><creatorcontrib>Luffer-Atlas, Debra</creatorcontrib><creatorcontrib>Dean, Brian J</creatorcontrib><creatorcontrib>McGowan, Erin M</creatorcontrib><creatorcontrib>Feeney, William P</creatorcontrib><creatorcontrib>Chiu, Shuet-Hing Lee</creatorcontrib><creatorcontrib>Cascieri, Margaret A</creatorcontrib><creatorcontrib>Chicchi, Gary G</creatorcontrib><creatorcontrib>Kurtz, Marc M</creatorcontrib><creatorcontrib>Sadowski, Sharon</creatorcontrib><creatorcontrib>Ber, Elzbieta</creatorcontrib><creatorcontrib>Tattersall, F. David</creatorcontrib><creatorcontrib>Rupniak, Nadia M. J</creatorcontrib><creatorcontrib>Williams, Angela R</creatorcontrib><creatorcontrib>Rycroft, Wayne</creatorcontrib><creatorcontrib>Hargreaves, Richard</creatorcontrib><creatorcontrib>Metzger, Joseph M</creatorcontrib><creatorcontrib>MacIntyre, D. Euan</creatorcontrib><title>Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-d-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-d-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.</description><subject>Acetals - chemical synthesis</subject><subject>Acetals - chemistry</subject><subject>Acetals - metabolism</subject><subject>Acetals - pharmacology</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - metabolism</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Antiemetics - chemical synthesis</subject><subject>Antiemetics - chemistry</subject><subject>Antiemetics - metabolism</subject><subject>Antiemetics - pharmacology</subject><subject>Antineoplastic Agents</subject><subject>Aprepitant</subject><subject>Biological and medical sciences</subject><subject>Cisplatin</subject><subject>Dogs</subject><subject>Drug Evaluation, Preclinical</subject><subject>Ferrets</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Morpholines - chemical synthesis</subject><subject>Morpholines - chemistry</subject><subject>Morpholines - metabolism</subject><subject>Morpholines - pharmacology</subject><subject>Neurokinin-1 Receptor Antagonists</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - pharmacology</subject><subject>Rats</subject><subject>Solubility</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Vomiting - chemically induced</subject><subject>Vomiting - drug therapy</subject><subject>Water</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0Mtu1DAUBmALgehQWPACyAtAYhHwseM4WY7KpaACA1MEYmM5vrSZOvZgJ4i-PUYZFRasrOPz6dfRj9BDIM-BUHixG7uONCB-3kIr4JRUdUvq22hFCKUVbSg7Qvdy3hFCGFB2Fx0BEUwI3qxQv7mMeX8Z07VXkzX4fUxl8kOweK3tpDw-nUcV8Ac7p3g1hCFUgD9bbfdTTHgdJnURw5CnjFXGX0tEqrbRz723eJOiSfNFvo_uOOWzfXB4j9GX16_OT06rs49v3p6szyrFRDtVzDUNB1azuqtdb4B20FvVCWh5x7hrXMdb6qgBYRkYbYQ1QtfUmBaUI-XzGD1dcvcp_phtnuQ4ZG29V8HGOUsBhHBOWIHPFqhTzDlZJ_dpGFW6lkDkn0LlTaHFPjqEzv1ozT9yabCAxwegslbeJRX0kP86RltgXWHVwkpX9tfNWqUr2ZQkLs83W_kOtuKl-PZJfi_-yeKVznIX5xRKdf-57zfpQJk1</recordid><startdate>20000323</startdate><enddate>20000323</enddate><creator>Hale, Jeffrey J</creator><creator>Mills, Sander G</creator><creator>MacCoss, Malcolm</creator><creator>Dorn, Conrad P</creator><creator>Finke, Paul E</creator><creator>Budhu, Richard J</creator><creator>Reamer, Robert A</creator><creator>Huskey, Su-Er W</creator><creator>Luffer-Atlas, Debra</creator><creator>Dean, Brian J</creator><creator>McGowan, Erin M</creator><creator>Feeney, William P</creator><creator>Chiu, Shuet-Hing Lee</creator><creator>Cascieri, Margaret A</creator><creator>Chicchi, Gary G</creator><creator>Kurtz, Marc M</creator><creator>Sadowski, Sharon</creator><creator>Ber, Elzbieta</creator><creator>Tattersall, F. David</creator><creator>Rupniak, Nadia M. J</creator><creator>Williams, Angela R</creator><creator>Rycroft, Wayne</creator><creator>Hargreaves, Richard</creator><creator>Metzger, Joseph M</creator><creator>MacIntyre, D. Euan</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>20000323</creationdate><title>Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs</title><author>Hale, Jeffrey J ; Mills, Sander G ; MacCoss, Malcolm ; Dorn, Conrad P ; Finke, Paul E ; Budhu, Richard J ; Reamer, Robert A ; Huskey, Su-Er W ; Luffer-Atlas, Debra ; Dean, Brian J ; McGowan, Erin M ; Feeney, William P ; Chiu, Shuet-Hing Lee ; Cascieri, Margaret A ; Chicchi, Gary G ; Kurtz, Marc M ; Sadowski, Sharon ; Ber, Elzbieta ; Tattersall, F. David ; Rupniak, Nadia M. J ; Williams, Angela R ; Rycroft, Wayne ; Hargreaves, Richard ; Metzger, Joseph M ; MacIntyre, D. 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Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - pharmacology</topic><topic>Rats</topic><topic>Solubility</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Vomiting - chemically induced</topic><topic>Vomiting - drug therapy</topic><topic>Water</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hale, Jeffrey J</creatorcontrib><creatorcontrib>Mills, Sander G</creatorcontrib><creatorcontrib>MacCoss, Malcolm</creatorcontrib><creatorcontrib>Dorn, Conrad P</creatorcontrib><creatorcontrib>Finke, Paul E</creatorcontrib><creatorcontrib>Budhu, Richard J</creatorcontrib><creatorcontrib>Reamer, Robert A</creatorcontrib><creatorcontrib>Huskey, Su-Er W</creatorcontrib><creatorcontrib>Luffer-Atlas, Debra</creatorcontrib><creatorcontrib>Dean, Brian J</creatorcontrib><creatorcontrib>McGowan, Erin M</creatorcontrib><creatorcontrib>Feeney, William P</creatorcontrib><creatorcontrib>Chiu, Shuet-Hing Lee</creatorcontrib><creatorcontrib>Cascieri, Margaret A</creatorcontrib><creatorcontrib>Chicchi, Gary G</creatorcontrib><creatorcontrib>Kurtz, Marc M</creatorcontrib><creatorcontrib>Sadowski, Sharon</creatorcontrib><creatorcontrib>Ber, Elzbieta</creatorcontrib><creatorcontrib>Tattersall, F. David</creatorcontrib><creatorcontrib>Rupniak, Nadia M. J</creatorcontrib><creatorcontrib>Williams, Angela R</creatorcontrib><creatorcontrib>Rycroft, Wayne</creatorcontrib><creatorcontrib>Hargreaves, Richard</creatorcontrib><creatorcontrib>Metzger, Joseph M</creatorcontrib><creatorcontrib>MacIntyre, D. Euan</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>Hale, Jeffrey J</au><au>Mills, Sander G</au><au>MacCoss, Malcolm</au><au>Dorn, Conrad P</au><au>Finke, Paul E</au><au>Budhu, Richard J</au><au>Reamer, Robert A</au><au>Huskey, Su-Er W</au><au>Luffer-Atlas, Debra</au><au>Dean, Brian J</au><au>McGowan, Erin M</au><au>Feeney, William P</au><au>Chiu, Shuet-Hing Lee</au><au>Cascieri, Margaret A</au><au>Chicchi, Gary G</au><au>Kurtz, Marc M</au><au>Sadowski, Sharon</au><au>Ber, Elzbieta</au><au>Tattersall, F. David</au><au>Rupniak, Nadia M. J</au><au>Williams, Angela R</au><au>Rycroft, Wayne</au><au>Hargreaves, Richard</au><au>Metzger, Joseph M</au><au>MacIntyre, D. Euan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2000-03-23</date><risdate>2000</risdate><volume>43</volume><issue>6</issue><spage>1234</spage><epage>1241</epage><pages>1234-1241</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-d-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-d-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10737756</pmid><doi>10.1021/jm990617v</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2000-03, Vol.43 (6), p.1234-1241 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_71005503 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Acetals - chemical synthesis Acetals - chemistry Acetals - metabolism Acetals - pharmacology Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - metabolism Anti-Inflammatory Agents, Non-Steroidal - pharmacology Antiemetics - chemical synthesis Antiemetics - chemistry Antiemetics - metabolism Antiemetics - pharmacology Antineoplastic Agents Aprepitant Biological and medical sciences Cisplatin Dogs Drug Evaluation, Preclinical Ferrets Guinea Pigs Humans Medical sciences Morpholines - chemical synthesis Morpholines - chemistry Morpholines - metabolism Morpholines - pharmacology Neurokinin-1 Receptor Antagonists Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - metabolism Prodrugs - pharmacology Rats Solubility Stereoisomerism Structure-Activity Relationship Vomiting - chemically induced Vomiting - drug therapy Water |
| title | Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T17%3A34%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phosphorylated%20Morpholine%20Acetal%20Human%20Neurokinin-1%20Receptor%20Antagonists%20as%20Water-Soluble%20Prodrugs&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Hale,%20Jeffrey%20J&rft.date=2000-03-23&rft.volume=43&rft.issue=6&rft.spage=1234&rft.epage=1241&rft.pages=1234-1241&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm990617v&rft_dat=%3Cproquest_cross%3E71005503%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=71005503&rft_id=info:pmid/10737756&rfr_iscdi=true |