Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors
SGK1 inhibitors 1 and 2 suffered from poor oral exposure that could be attributed to factors such as high clearance and formation of glucuronic acid conjugates. Incorporation of appropriately-placed substituents was an effective means of reducing clearance and, in some cases, suppressing glucuronida...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (15), p.4441-4445 |
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| creator | Hammond, Marlys Washburn, David G. Hoang, Tram H. Manns, Sharada Frazee, James S. Nakamura, Hiroko Patterson, Jaclyn R. Trizna, Walter Wu, Charlene Azzarano, Leonard M. Nagilla, Rakesh Nord, Melanie Trejo, Rebecca Head, Martha S. Zhao, Baoguang Smallwood, Angela M. Hightower, Kendra Laping, Nicholas J. Schnackenberg, Christine G. Thompson, Scott K. |
| description | SGK1 inhibitors 1 and 2 suffered from poor oral exposure that could be attributed to factors such as high clearance and formation of glucuronic acid conjugates. Incorporation of appropriately-placed substituents was an effective means of reducing clearance and, in some cases, suppressing glucuronidation to provide SGK1 inhibitors with adequate exposure for in vivo studies.
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing. |
| doi_str_mv | 10.1016/j.bmcl.2009.05.051 |
| format | Article |
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The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.05.051</identifier><identifier>PMID: 19497745</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Analytical, structural and metabolic biochemistry ; Animals ; BASIC BIOLOGICAL SCIENCES ; Biological and medical sciences ; Biological Availability ; Chemistry, Pharmaceutical - methods ; DESIGN ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacology ; Enzymes and enzyme inhibitors ; EXCRETION ; Fundamental and applied biological sciences. Psychology ; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE ; Glucocorticoids - chemistry ; GLUCURONIC ACID ; Glucuronic Acid - chemistry ; Glucuronidation ; Immediate-Early Proteins - antagonists & inhibitors ; Immediate-Early Proteins - chemistry ; IN VIVO ; Inhibitory Concentration 50 ; Kinase inhibitor ; Medical sciences ; Miscellaneous ; Models, Chemical ; Molecular Conformation ; Pharmacology. Drug treatments ; PHOSPHOTRANSFERASES ; Protein Kinase Inhibitors - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - chemistry ; Rats ; Serum and glucocorticoid-regulated kinase ; SGK1 ; Structure-Activity Relationship ; SYNTHESIS ; TESTING ; Transferases</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-08, Vol.19 (15), p.4441-4445</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-4b79fbef37bd86146e318430bd900c2adf738e367c680c7eb1d1a22d391ef0b23</citedby><cites>FETCH-LOGICAL-c443t-4b79fbef37bd86146e318430bd900c2adf738e367c680c7eb1d1a22d391ef0b23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09007264$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21749156$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19497745$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1006153$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Hammond, Marlys</creatorcontrib><creatorcontrib>Washburn, David G.</creatorcontrib><creatorcontrib>Hoang, Tram H.</creatorcontrib><creatorcontrib>Manns, Sharada</creatorcontrib><creatorcontrib>Frazee, James S.</creatorcontrib><creatorcontrib>Nakamura, Hiroko</creatorcontrib><creatorcontrib>Patterson, Jaclyn R.</creatorcontrib><creatorcontrib>Trizna, Walter</creatorcontrib><creatorcontrib>Wu, Charlene</creatorcontrib><creatorcontrib>Azzarano, Leonard M.</creatorcontrib><creatorcontrib>Nagilla, Rakesh</creatorcontrib><creatorcontrib>Nord, Melanie</creatorcontrib><creatorcontrib>Trejo, Rebecca</creatorcontrib><creatorcontrib>Head, Martha S.</creatorcontrib><creatorcontrib>Zhao, Baoguang</creatorcontrib><creatorcontrib>Smallwood, Angela M.</creatorcontrib><creatorcontrib>Hightower, Kendra</creatorcontrib><creatorcontrib>Laping, Nicholas J.</creatorcontrib><creatorcontrib>Schnackenberg, Christine G.</creatorcontrib><creatorcontrib>Thompson, Scott K.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States)</creatorcontrib><title>Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>SGK1 inhibitors 1 and 2 suffered from poor oral exposure that could be attributed to factors such as high clearance and formation of glucuronic acid conjugates. Incorporation of appropriately-placed substituents was an effective means of reducing clearance and, in some cases, suppressing glucuronidation to provide SGK1 inhibitors with adequate exposure for in vivo studies.
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.</description><subject>Administration, Oral</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>DESIGN</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzymes and enzyme inhibitors</subject><subject>EXCRETION</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE</subject><subject>Glucocorticoids - chemistry</subject><subject>GLUCURONIC ACID</subject><subject>Glucuronic Acid - chemistry</subject><subject>Glucuronidation</subject><subject>Immediate-Early Proteins - antagonists & inhibitors</subject><subject>Immediate-Early Proteins - chemistry</subject><subject>IN VIVO</subject><subject>Inhibitory Concentration 50</subject><subject>Kinase inhibitor</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>PHOSPHOTRANSFERASES</subject><subject>Protein Kinase Inhibitors - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - chemistry</subject><subject>Rats</subject><subject>Serum and glucocorticoid-regulated kinase</subject><subject>SGK1</subject><subject>Structure-Activity Relationship</subject><subject>SYNTHESIS</subject><subject>TESTING</subject><subject>Transferases</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU-LFDEQxYMo7uzqF_AgQVD00GOlk-6egBfZ1VVc8KCCtyZ_qmcyppPdpHthvr1pZ9CbUFAU_OpRrx4hzxisGbD27X6tR-PXNYBcQ1OKPSArJlpRcQHNQ7IC2UK1keLnGTnPeQ_ABAjxmJwxKWTXiWZF3BVmtw1UBUvzIUy7MmYaBxqT8v5AtYvqXjmvtEeaMc3jH3TrZxNNTJMz0dkq4Xb2akJLf7mgMlJGX3-7_sLeUBd2TrsppvyEPBqUz_j01C_Ij48fvl9-qm6-Xn--fH9TGSH4VAndyUHjwDttN21xg5xtBAdtJYCplR06vkHedqbdgOlQM8tUXVsuGQ6ga35BXhx1Y55cn42b0OxMDAHN1DOAljW8QK-O0G2KdzPmqR9dNui9Chjn3NfAmlbyroD1ETQp5pxw6G-TG1U6FKl-SaHf90sK_ZJCD00pVpaen9RnPaL9t3J6ewFengCVjfJDUsG4_JerWSdkOaBw744clofdO0yLHwwGrUuLHRvd_-74DRJgpas</recordid><startdate>20090801</startdate><enddate>20090801</enddate><creator>Hammond, Marlys</creator><creator>Washburn, David G.</creator><creator>Hoang, Tram H.</creator><creator>Manns, Sharada</creator><creator>Frazee, James S.</creator><creator>Nakamura, Hiroko</creator><creator>Patterson, Jaclyn R.</creator><creator>Trizna, Walter</creator><creator>Wu, Charlene</creator><creator>Azzarano, Leonard M.</creator><creator>Nagilla, Rakesh</creator><creator>Nord, Melanie</creator><creator>Trejo, Rebecca</creator><creator>Head, Martha S.</creator><creator>Zhao, Baoguang</creator><creator>Smallwood, Angela M.</creator><creator>Hightower, Kendra</creator><creator>Laping, Nicholas J.</creator><creator>Schnackenberg, Christine G.</creator><creator>Thompson, Scott K.</creator><general>Elsevier Ltd</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>OTOTI</scope></search><sort><creationdate>20090801</creationdate><title>Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors</title><author>Hammond, Marlys ; Washburn, David G. ; Hoang, Tram H. ; Manns, Sharada ; Frazee, James S. ; Nakamura, Hiroko ; Patterson, Jaclyn R. ; Trizna, Walter ; Wu, Charlene ; Azzarano, Leonard M. ; Nagilla, Rakesh ; Nord, Melanie ; Trejo, Rebecca ; Head, Martha S. ; Zhao, Baoguang ; Smallwood, Angela M. ; Hightower, Kendra ; Laping, Nicholas J. ; Schnackenberg, Christine G. ; Thompson, Scott K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-4b79fbef37bd86146e318430bd900c2adf738e367c680c7eb1d1a22d391ef0b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>DESIGN</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzymes and enzyme inhibitors</topic><topic>EXCRETION</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE</topic><topic>Glucocorticoids - chemistry</topic><topic>GLUCURONIC ACID</topic><topic>Glucuronic Acid - chemistry</topic><topic>Glucuronidation</topic><topic>Immediate-Early Proteins - antagonists & inhibitors</topic><topic>Immediate-Early Proteins - chemistry</topic><topic>IN VIVO</topic><topic>Inhibitory Concentration 50</topic><topic>Kinase inhibitor</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Models, Chemical</topic><topic>Molecular Conformation</topic><topic>Pharmacology. Drug treatments</topic><topic>PHOSPHOTRANSFERASES</topic><topic>Protein Kinase Inhibitors - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Rats</topic><topic>Serum and glucocorticoid-regulated kinase</topic><topic>SGK1</topic><topic>Structure-Activity Relationship</topic><topic>SYNTHESIS</topic><topic>TESTING</topic><topic>Transferases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hammond, Marlys</creatorcontrib><creatorcontrib>Washburn, David G.</creatorcontrib><creatorcontrib>Hoang, Tram H.</creatorcontrib><creatorcontrib>Manns, Sharada</creatorcontrib><creatorcontrib>Frazee, James S.</creatorcontrib><creatorcontrib>Nakamura, Hiroko</creatorcontrib><creatorcontrib>Patterson, Jaclyn R.</creatorcontrib><creatorcontrib>Trizna, Walter</creatorcontrib><creatorcontrib>Wu, Charlene</creatorcontrib><creatorcontrib>Azzarano, Leonard M.</creatorcontrib><creatorcontrib>Nagilla, Rakesh</creatorcontrib><creatorcontrib>Nord, Melanie</creatorcontrib><creatorcontrib>Trejo, Rebecca</creatorcontrib><creatorcontrib>Head, Martha S.</creatorcontrib><creatorcontrib>Zhao, Baoguang</creatorcontrib><creatorcontrib>Smallwood, Angela M.</creatorcontrib><creatorcontrib>Hightower, Kendra</creatorcontrib><creatorcontrib>Laping, Nicholas J.</creatorcontrib><creatorcontrib>Schnackenberg, Christine G.</creatorcontrib><creatorcontrib>Thompson, Scott K.</creatorcontrib><creatorcontrib>Argonne National Lab. 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(ANL), Argonne, IL (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-08-01</date><risdate>2009</risdate><volume>19</volume><issue>15</issue><spage>4441</spage><epage>4445</epage><pages>4441-4445</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>SGK1 inhibitors 1 and 2 suffered from poor oral exposure that could be attributed to factors such as high clearance and formation of glucuronic acid conjugates. Incorporation of appropriately-placed substituents was an effective means of reducing clearance and, in some cases, suppressing glucuronidation to provide SGK1 inhibitors with adequate exposure for in vivo studies.
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19497745</pmid><doi>10.1016/j.bmcl.2009.05.051</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2009-08, Vol.19 (15), p.4441-4445 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| subjects | Administration, Oral Analytical, structural and metabolic biochemistry Animals BASIC BIOLOGICAL SCIENCES Biological and medical sciences Biological Availability Chemistry, Pharmaceutical - methods DESIGN Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Enzymes and enzyme inhibitors EXCRETION Fundamental and applied biological sciences. Psychology GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE Glucocorticoids - chemistry GLUCURONIC ACID Glucuronic Acid - chemistry Glucuronidation Immediate-Early Proteins - antagonists & inhibitors Immediate-Early Proteins - chemistry IN VIVO Inhibitory Concentration 50 Kinase inhibitor Medical sciences Miscellaneous Models, Chemical Molecular Conformation Pharmacology. Drug treatments PHOSPHOTRANSFERASES Protein Kinase Inhibitors - antagonists & inhibitors Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - chemistry Rats Serum and glucocorticoid-regulated kinase SGK1 Structure-Activity Relationship SYNTHESIS TESTING Transferases |
| title | Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors |
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