Short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives as orally-active calcium-sensing receptor antagonists
Structure–activity relationship studies, focused on the optimization of pharmacology and pharmacokinetics, are described for a series of short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives and calcium-sensing receptor antagonists. Synthesis and structure–activity relations...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4555-4559 |
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| creator | Didiuk, Mary T. Griffith, David A. Benbow, John W. Liu, Kevin K.C. Walker, Daniel P. Christopher Bi, F. Morris, Joel Guzman-Perez, Angel Gao, Hua Bechle, Bruce M. Kelley, Ryan M. Yang, Xiaojing Dirico, Kenneth Ahmed, Syed Hungerford, William DiBrinno, Joseph Zawistoski, Michael P. Bagley, Scott W. Li, Jianke Zeng, Yuan Santucci, Stephanie Oliver, Robert Corbett, Matthew Olson, Thanh Chen, Chiliu Li, Mei Paralkar, Vishwas M. Riccardi, Keith A. Healy, David R. Kalgutkar, Amit S. Maurer, Tristan S. Nguyen, Hang T. Frederick, Kosea S. |
| description | Structure–activity relationship studies, focused on the optimization of pharmacology and pharmacokinetics, are described for a series of short-acting 5-(trifluoromethyl)pyrido[4,3-
d]pyrimidin-4(3
H)-one derivatives and calcium-sensing receptor antagonists.
Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-
d]pyrimidin-4(3
H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects. |
| doi_str_mv | 10.1016/j.bmcl.2009.07.004 |
| format | Article |
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d]pyrimidin-4(3
H)-one derivatives and calcium-sensing receptor antagonists.
Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-
d]pyrimidin-4(3
H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.07.004</identifier><identifier>PMID: 19625189</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Anabolic Agents - administration & dosage ; Anabolic Agents - chemistry ; Anabolic Agents - pharmacokinetics ; Animals ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Calcium receptor antagonists ; Human parathyroid hormone ; Male ; Medical sciences ; Osteoporosis ; Parathyroid Hormone - metabolism ; Pharmacokinetics ; Pharmacology. Drug treatments ; Pyrimidinones - administration & dosage ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Receptors, Calcium-Sensing - antagonists & inhibitors ; Receptors, Calcium-Sensing - metabolism ; SAR exploration ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-08, Vol.19 (16), p.4555-4559</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-59cbdde85819fdaf77a20aab8f21b58eff1592744585a46f9663e3c6b1129e0d3</citedby><cites>FETCH-LOGICAL-c415t-59cbdde85819fdaf77a20aab8f21b58eff1592744585a46f9663e3c6b1129e0d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09009548$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21799080$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19625189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Didiuk, Mary T.</creatorcontrib><creatorcontrib>Griffith, David A.</creatorcontrib><creatorcontrib>Benbow, John W.</creatorcontrib><creatorcontrib>Liu, Kevin K.C.</creatorcontrib><creatorcontrib>Walker, Daniel P.</creatorcontrib><creatorcontrib>Christopher Bi, F.</creatorcontrib><creatorcontrib>Morris, Joel</creatorcontrib><creatorcontrib>Guzman-Perez, Angel</creatorcontrib><creatorcontrib>Gao, Hua</creatorcontrib><creatorcontrib>Bechle, Bruce M.</creatorcontrib><creatorcontrib>Kelley, Ryan M.</creatorcontrib><creatorcontrib>Yang, Xiaojing</creatorcontrib><creatorcontrib>Dirico, Kenneth</creatorcontrib><creatorcontrib>Ahmed, Syed</creatorcontrib><creatorcontrib>Hungerford, William</creatorcontrib><creatorcontrib>DiBrinno, Joseph</creatorcontrib><creatorcontrib>Zawistoski, Michael P.</creatorcontrib><creatorcontrib>Bagley, Scott W.</creatorcontrib><creatorcontrib>Li, Jianke</creatorcontrib><creatorcontrib>Zeng, Yuan</creatorcontrib><creatorcontrib>Santucci, Stephanie</creatorcontrib><creatorcontrib>Oliver, Robert</creatorcontrib><creatorcontrib>Corbett, Matthew</creatorcontrib><creatorcontrib>Olson, Thanh</creatorcontrib><creatorcontrib>Chen, Chiliu</creatorcontrib><creatorcontrib>Li, Mei</creatorcontrib><creatorcontrib>Paralkar, Vishwas M.</creatorcontrib><creatorcontrib>Riccardi, Keith A.</creatorcontrib><creatorcontrib>Healy, David R.</creatorcontrib><creatorcontrib>Kalgutkar, Amit S.</creatorcontrib><creatorcontrib>Maurer, Tristan S.</creatorcontrib><creatorcontrib>Nguyen, Hang T.</creatorcontrib><creatorcontrib>Frederick, Kosea S.</creatorcontrib><title>Short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives as orally-active calcium-sensing receptor antagonists</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Structure–activity relationship studies, focused on the optimization of pharmacology and pharmacokinetics, are described for a series of short-acting 5-(trifluoromethyl)pyrido[4,3-
d]pyrimidin-4(3
H)-one derivatives and calcium-sensing receptor antagonists.
Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-
d]pyrimidin-4(3
H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.</description><subject>Administration, Oral</subject><subject>Anabolic Agents - administration & dosage</subject><subject>Anabolic Agents - chemistry</subject><subject>Anabolic Agents - pharmacokinetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Calcium receptor antagonists</subject><subject>Human parathyroid hormone</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Osteoporosis</subject><subject>Parathyroid Hormone - metabolism</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrimidinones - administration & dosage</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Calcium-Sensing - antagonists & inhibitors</subject><subject>Receptors, Calcium-Sensing - metabolism</subject><subject>SAR exploration</subject><subject>Structure-Activity Relationship</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>eNqFkUGL1DAYhoMo7rj6BzxIL8oumJqkSZqAF1nUFRY8qCCIhDT5upuhbcYkHZi7P9zWGfSmp_DB871feB-EnlJSU0Llq23djW6oGSG6Jm1NCL-HNpRLjhtOxH20IVoSrDT_eoYe5bwlhHLC-UN0RrVkgiq9QT8_3cVUsHUlTLeVwBclhX6YY4ojlLvDcLk7pODjN_6ywZX_vk5j8GHC_KKpri9xnKDykMLelrCHXNlcxWSH4fA7cg-Vs4ML84gzTHk9kcDBrsRU2anY2ziFXPJj9KC3Q4Ynp_ccfXn39vPVNb75-P7D1Zsb7DgVBQvtOu9BCUV1723ftpYRazvVM9oJBX1PhWYt50IJy2WvpWygcbKjlGkgvjlHL465uxR_zJCLGUN2MAx2gjhnI1vRNIqr_4KMMCpVSxaQHUGXYs4JerNbCrLpYCgxqySzNasks0oypDWLpGXp2Sl97kbwf1dOVhbg-QmweemvT3ZyIf_hGG21Jmq9_vrIwVLaPkAy2QWYHPiw1FyMj-Ff__gF9nGxjA</recordid><startdate>20090815</startdate><enddate>20090815</enddate><creator>Didiuk, Mary T.</creator><creator>Griffith, David A.</creator><creator>Benbow, John W.</creator><creator>Liu, Kevin K.C.</creator><creator>Walker, Daniel P.</creator><creator>Christopher Bi, F.</creator><creator>Morris, Joel</creator><creator>Guzman-Perez, Angel</creator><creator>Gao, Hua</creator><creator>Bechle, Bruce M.</creator><creator>Kelley, Ryan M.</creator><creator>Yang, Xiaojing</creator><creator>Dirico, Kenneth</creator><creator>Ahmed, Syed</creator><creator>Hungerford, William</creator><creator>DiBrinno, Joseph</creator><creator>Zawistoski, Michael P.</creator><creator>Bagley, Scott W.</creator><creator>Li, Jianke</creator><creator>Zeng, Yuan</creator><creator>Santucci, Stephanie</creator><creator>Oliver, Robert</creator><creator>Corbett, Matthew</creator><creator>Olson, Thanh</creator><creator>Chen, Chiliu</creator><creator>Li, Mei</creator><creator>Paralkar, Vishwas M.</creator><creator>Riccardi, Keith A.</creator><creator>Healy, David R.</creator><creator>Kalgutkar, Amit S.</creator><creator>Maurer, Tristan S.</creator><creator>Nguyen, Hang T.</creator><creator>Frederick, Kosea S.</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>7QP</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20090815</creationdate><title>Short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives as orally-active calcium-sensing receptor antagonists</title><author>Didiuk, Mary T. ; Griffith, David A. ; Benbow, John W. ; Liu, Kevin K.C. ; Walker, Daniel P. ; Christopher Bi, F. ; Morris, Joel ; Guzman-Perez, Angel ; Gao, Hua ; Bechle, Bruce M. ; Kelley, Ryan M. ; Yang, Xiaojing ; Dirico, Kenneth ; Ahmed, Syed ; Hungerford, William ; DiBrinno, Joseph ; Zawistoski, Michael P. ; Bagley, Scott W. ; Li, Jianke ; Zeng, Yuan ; Santucci, Stephanie ; Oliver, Robert ; Corbett, Matthew ; Olson, Thanh ; Chen, Chiliu ; Li, Mei ; Paralkar, Vishwas M. ; Riccardi, Keith A. ; Healy, David R. ; Kalgutkar, Amit S. ; Maurer, Tristan S. ; Nguyen, Hang T. ; Frederick, Kosea S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-59cbdde85819fdaf77a20aab8f21b58eff1592744585a46f9663e3c6b1129e0d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Anabolic Agents - administration & dosage</topic><topic>Anabolic Agents - chemistry</topic><topic>Anabolic Agents - pharmacokinetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Calcium receptor antagonists</topic><topic>Human parathyroid hormone</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Osteoporosis</topic><topic>Parathyroid Hormone - metabolism</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. 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d]pyrimidin-4(3
H)-one derivatives and calcium-sensing receptor antagonists.
Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-
d]pyrimidin-4(3
H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19625189</pmid><doi>10.1016/j.bmcl.2009.07.004</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2009-08, Vol.19 (16), p.4555-4559 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67533848 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Administration, Oral Anabolic Agents - administration & dosage Anabolic Agents - chemistry Anabolic Agents - pharmacokinetics Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Calcium receptor antagonists Human parathyroid hormone Male Medical sciences Osteoporosis Parathyroid Hormone - metabolism Pharmacokinetics Pharmacology. Drug treatments Pyrimidinones - administration & dosage Pyrimidinones - chemistry Pyrimidinones - pharmacokinetics Rats Rats, Sprague-Dawley Receptors, Calcium-Sensing - antagonists & inhibitors Receptors, Calcium-Sensing - metabolism SAR exploration Structure-Activity Relationship |
| title | Short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives as orally-active calcium-sensing receptor antagonists |
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