Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydro...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2006-06, Vol.16 (12), p.3175-3179 |
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| creator | COX, Christopher D TORRENT, Maricel LOBELL, Robert B WEIKANG TAO SOUTH, Vicki J KOHL, Nancy E YOUWEI YAN KUO, Lawrence C PRUEKSARITANONT, Thomayant SLAUGHTER, Donald E CHUNZE LI MAHAN, Elizabeth BRESLIN, Michael J BING LU HARTMAN, George D MARIANO, Brenda J WHITMAN, David B COLEMAN, Paul J BUSER, Carolyn A WALSH, Eileen S HAMILTON, Kelly SCHABER, Michael D |
| description | Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound. |
| doi_str_mv | 10.1016/j.bmcl.2006.03.040 |
| format | Article |
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Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>COX, Christopher D ; TORRENT, Maricel ; LOBELL, Robert B ; WEIKANG TAO ; SOUTH, Vicki J ; KOHL, Nancy E ; YOUWEI YAN ; KUO, Lawrence C ; PRUEKSARITANONT, Thomayant ; SLAUGHTER, Donald E ; CHUNZE LI ; MAHAN, Elizabeth ; BRESLIN, Michael J ; BING LU ; HARTMAN, George D ; MARIANO, Brenda J ; WHITMAN, David B ; COLEMAN, Paul J ; BUSER, Carolyn A ; WALSH, Eileen S ; HAMILTON, Kelly ; SCHABER, Michael D</creator><creatorcontrib>COX, Christopher D ; TORRENT, Maricel ; LOBELL, Robert B ; WEIKANG TAO ; SOUTH, Vicki J ; KOHL, Nancy E ; YOUWEI YAN ; KUO, Lawrence C ; PRUEKSARITANONT, Thomayant ; SLAUGHTER, Donald E ; CHUNZE LI ; MAHAN, Elizabeth ; BRESLIN, Michael J ; BING LU ; HARTMAN, George D ; MARIANO, Brenda J ; WHITMAN, David B ; COLEMAN, Paul J ; BUSER, Carolyn A ; WALSH, Eileen S ; HAMILTON, Kelly ; SCHABER, Michael D</creatorcontrib><description>Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2006.03.040</identifier><identifier>PMID: 16603356</identifier><language>eng</language><publisher>Oxford: Elsevier</publisher><subject>Alkylation ; Allosteric Site ; Amination ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Crystallography, X-Ray ; Dogs ; Drug Design ; General aspects ; Hydroxylation ; Kinesin - antagonists & inhibitors ; Kinesin - chemistry ; Kinesin - metabolism ; Medical sciences ; Mitosis ; Models, Molecular ; Molecular Structure ; Pharmacology. Drug treatments ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Solubility ; Structure-Activity Relationship ; Water</subject><ispartof>Bioorganic & medicinal chemistry letters, 2006-06, Vol.16 (12), p.3175-3179</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-26ea5b400ba43bc0cd5f3a7feee4a3592fa2da7f09bf1a6275cab34c67fc3e2e3</citedby><cites>FETCH-LOGICAL-c428t-26ea5b400ba43bc0cd5f3a7feee4a3592fa2da7f09bf1a6275cab34c67fc3e2e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17758867$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16603356$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>COX, Christopher D</creatorcontrib><creatorcontrib>TORRENT, Maricel</creatorcontrib><creatorcontrib>LOBELL, Robert B</creatorcontrib><creatorcontrib>WEIKANG TAO</creatorcontrib><creatorcontrib>SOUTH, Vicki J</creatorcontrib><creatorcontrib>KOHL, Nancy E</creatorcontrib><creatorcontrib>YOUWEI YAN</creatorcontrib><creatorcontrib>KUO, Lawrence C</creatorcontrib><creatorcontrib>PRUEKSARITANONT, Thomayant</creatorcontrib><creatorcontrib>SLAUGHTER, Donald E</creatorcontrib><creatorcontrib>CHUNZE LI</creatorcontrib><creatorcontrib>MAHAN, Elizabeth</creatorcontrib><creatorcontrib>BRESLIN, Michael J</creatorcontrib><creatorcontrib>BING LU</creatorcontrib><creatorcontrib>HARTMAN, George D</creatorcontrib><creatorcontrib>MARIANO, Brenda J</creatorcontrib><creatorcontrib>WHITMAN, David B</creatorcontrib><creatorcontrib>COLEMAN, Paul J</creatorcontrib><creatorcontrib>BUSER, Carolyn A</creatorcontrib><creatorcontrib>WALSH, Eileen S</creatorcontrib><creatorcontrib>HAMILTON, Kelly</creatorcontrib><creatorcontrib>SCHABER, Michael D</creatorcontrib><title>Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.</description><subject>Alkylation</subject><subject>Allosteric Site</subject><subject>Amination</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>General aspects</subject><subject>Hydroxylation</subject><subject>Kinesin - antagonists & inhibitors</subject><subject>Kinesin - chemistry</subject><subject>Kinesin - metabolism</subject><subject>Medical sciences</subject><subject>Mitosis</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Water</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUctqFTEYDqLY0-oLuJBslArN-GeSycy4k-KNFixUwV1IMhlPTjOXJhnk-GK-njl24CxdJR98N_4PoRcUCgpUvN0VejC-KAFEAawADo_QhnLBCeNQPUYbaAWQpuU_TtBpjDsAyoHzp-iECgGMVWKD_ly50UY34ji7sfMWz2FKNuPzq9ubN9iNW6ddmkIs8I0KCfN3-DaFxaQlWKJVtB3usv7niKceV0T5u71Xgxsnwi4q0jkV9p7wf9_tvgvTvA_q9-RtxCriOUeN6QL_UskGEie_6NzgmHnwTFuLh4ySM_hu7ZqrPUNPeuWjfb6-Z-j7xw_fLj-T66-fvly-vyaGl00ipbCq0hxAK860AdNVPVN1b63lilVt2auyyxha3VMlyroySjNuRN0bZkvLztDrB998l_vFxiQHF431Xo12WqIUdcsaaJv_EmlNRVPXVSaWD0QTphiD7eUc3JDvJCnIw65yJw-7ysOuEpjMu2bRy9V90YPtjpJ1yEx4tRJUNMr3QY3GxSMvJzeNqNlfEgev3A</recordid><startdate>20060615</startdate><enddate>20060615</enddate><creator>COX, Christopher D</creator><creator>TORRENT, Maricel</creator><creator>LOBELL, Robert B</creator><creator>WEIKANG TAO</creator><creator>SOUTH, Vicki J</creator><creator>KOHL, Nancy E</creator><creator>YOUWEI YAN</creator><creator>KUO, Lawrence C</creator><creator>PRUEKSARITANONT, Thomayant</creator><creator>SLAUGHTER, Donald E</creator><creator>CHUNZE LI</creator><creator>MAHAN, Elizabeth</creator><creator>BRESLIN, Michael J</creator><creator>BING LU</creator><creator>HARTMAN, George D</creator><creator>MARIANO, Brenda J</creator><creator>WHITMAN, David B</creator><creator>COLEMAN, Paul J</creator><creator>BUSER, Carolyn A</creator><creator>WALSH, Eileen S</creator><creator>HAMILTON, Kelly</creator><creator>SCHABER, Michael D</creator><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>7X8</scope></search><sort><creationdate>20060615</creationdate><title>Kinesin spindle protein (KSP) inhibitors. 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Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2006-06-15</date><risdate>2006</risdate><volume>16</volume><issue>12</issue><spage>3175</spage><epage>3179</epage><pages>3175-3179</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.</abstract><cop>Oxford</cop><pub>Elsevier</pub><pmid>16603356</pmid><doi>10.1016/j.bmcl.2006.03.040</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2006-06, Vol.16 (12), p.3175-3179 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Alkylation Allosteric Site Amination Animals Antineoplastic agents Biological and medical sciences Crystallography, X-Ray Dogs Drug Design General aspects Hydroxylation Kinesin - antagonists & inhibitors Kinesin - chemistry Kinesin - metabolism Medical sciences Mitosis Models, Molecular Molecular Structure Pharmacology. Drug treatments Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Solubility Structure-Activity Relationship Water |
| title | Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP |
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