Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides
1‐Phenyl‐4‐piperazinyl‐carbonyl‐substituted nitrogen‐containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D‐24203, proved to be a potent inhibitor of in viv...
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| Veröffentlicht in: | Archiv der Pharmazie (Weinheim) 2004-12, Vol.337 (12), p.695-703 |
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| container_title | Archiv der Pharmazie (Weinheim) |
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| creator | Gerlach, Matthias Claus, Eckhard Baasner, Silke Müller, Gilbert Polymeropoulos, Emmanuel Schmidt, Peter Günther, Eckhard Engel, Jürgen |
| description | 1‐Phenyl‐4‐piperazinyl‐carbonyl‐substituted nitrogen‐containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D‐24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties.
Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization. |
| doi_str_mv | 10.1002/ardp.200400623 |
| format | Article |
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Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization.</description><identifier>ISSN: 0365-6233</identifier><identifier>EISSN: 1521-4184</identifier><identifier>DOI: 10.1002/ardp.200400623</identifier><identifier>PMID: 15597403</identifier><identifier>CODEN: ARPMAS</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Automated synthesis ; Binding, Competitive ; Biological and medical sciences ; Cell Line, Tumor ; Cell Survival - drug effects ; Colchicine - pharmacology ; Cytotoxic activity ; Drug Design ; Drug Screening Assays, Antitumor ; Focused library ; General aspects ; Humans ; Inhibitory Concentration 50 ; Ketopiperazides ; Medical sciences ; Mice ; Molecular Structure ; Pharmacology. Drug treatments ; Piperazines - chemical synthesis ; Piperazines - chemistry ; Piperazines - pharmacology ; Rats ; Solubility ; Tubulin - metabolism ; Tubulin polymerization inhibitor</subject><ispartof>Archiv der Pharmazie (Weinheim), 2004-12, Vol.337 (12), p.695-703</ispartof><rights>Copyright © 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4113-8cdd72d92808aa5c43e27abefda237c8dc9aa82f8bb5241c7bf69abd015a23213</citedby><cites>FETCH-LOGICAL-c4113-8cdd72d92808aa5c43e27abefda237c8dc9aa82f8bb5241c7bf69abd015a23213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fardp.200400623$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fardp.200400623$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27922,27923,45572,45573</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16386166$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15597403$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gerlach, Matthias</creatorcontrib><creatorcontrib>Claus, Eckhard</creatorcontrib><creatorcontrib>Baasner, Silke</creatorcontrib><creatorcontrib>Müller, Gilbert</creatorcontrib><creatorcontrib>Polymeropoulos, Emmanuel</creatorcontrib><creatorcontrib>Schmidt, Peter</creatorcontrib><creatorcontrib>Günther, Eckhard</creatorcontrib><creatorcontrib>Engel, Jürgen</creatorcontrib><title>Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides</title><title>Archiv der Pharmazie (Weinheim)</title><addtitle>Arch. Pharm. Pharm. Med. Chem</addtitle><description>1‐Phenyl‐4‐piperazinyl‐carbonyl‐substituted nitrogen‐containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D‐24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties.
Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Automated synthesis</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Colchicine - pharmacology</subject><subject>Cytotoxic activity</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Focused library</subject><subject>General aspects</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Ketopiperazides</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>Rats</subject><subject>Solubility</subject><subject>Tubulin - metabolism</subject><subject>Tubulin polymerization inhibitor</subject><issn>0365-6233</issn><issn>1521-4184</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkElPwzAQRi0EgrJcOaJcOKZ4iR3nWChtERWgst6sie1AICSRXZby60lIRblxGs3ovZnRh9A-wX2CMT0CZ-o-xTjCWFC2hnqEUxJGREbrqIeZ4GEzZlto2_tnjDHDlG-iLcJ5EkeY9dD90Pr8sQygNMH1opw_Na0PqiyAYFTpN29NMM1TB27RDi-qd1sEA7cowh9jYufWVdD253Ze1XltHXzlxvpdtJFB4e3esu6g29HpzckknF6Oz04G01BHhLBQamNiahIqsQTgOmKWxpDazABlsZZGJwCSZjJNOY2IjtNMJJAaTHgDUMJ2UL_bq13lvbOZql3-2nykCFZtQqpNSP0m1AgHnVC_pa_WrPBlJA1wuATAaygyB6XO_YoTTAoiRMMlHfeRF3bxz1k1mA2v_j4Rdm7u5_bz1wX3okTMYq7uL8ZqJuX47lg8qAn7BvuJjy8</recordid><startdate>200412</startdate><enddate>200412</enddate><creator>Gerlach, Matthias</creator><creator>Claus, Eckhard</creator><creator>Baasner, Silke</creator><creator>Müller, Gilbert</creator><creator>Polymeropoulos, Emmanuel</creator><creator>Schmidt, Peter</creator><creator>Günther, Eckhard</creator><creator>Engel, Jürgen</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><general>Wiley-VCH</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></search><sort><creationdate>200412</creationdate><title>Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides</title><author>Gerlach, Matthias ; Claus, Eckhard ; Baasner, Silke ; Müller, Gilbert ; Polymeropoulos, Emmanuel ; Schmidt, Peter ; Günther, Eckhard ; Engel, Jürgen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4113-8cdd72d92808aa5c43e27abefda237c8dc9aa82f8bb5241c7bf69abd015a23213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Automated synthesis</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Colchicine - pharmacology</topic><topic>Cytotoxic activity</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Focused library</topic><topic>General aspects</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Ketopiperazides</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>Rats</topic><topic>Solubility</topic><topic>Tubulin - metabolism</topic><topic>Tubulin polymerization inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gerlach, Matthias</creatorcontrib><creatorcontrib>Claus, Eckhard</creatorcontrib><creatorcontrib>Baasner, Silke</creatorcontrib><creatorcontrib>Müller, Gilbert</creatorcontrib><creatorcontrib>Polymeropoulos, Emmanuel</creatorcontrib><creatorcontrib>Schmidt, Peter</creatorcontrib><creatorcontrib>Günther, Eckhard</creatorcontrib><creatorcontrib>Engel, Jürgen</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><jtitle>Archiv der Pharmazie (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gerlach, Matthias</au><au>Claus, Eckhard</au><au>Baasner, Silke</au><au>Müller, Gilbert</au><au>Polymeropoulos, Emmanuel</au><au>Schmidt, Peter</au><au>Günther, Eckhard</au><au>Engel, Jürgen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides</atitle><jtitle>Archiv der Pharmazie (Weinheim)</jtitle><addtitle>Arch. 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Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties.
Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>15597403</pmid><doi>10.1002/ardp.200400623</doi><tpages>9</tpages></addata></record> |
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| ispartof | Archiv der Pharmazie (Weinheim), 2004-12, Vol.337 (12), p.695-703 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Automated synthesis Binding, Competitive Biological and medical sciences Cell Line, Tumor Cell Survival - drug effects Colchicine - pharmacology Cytotoxic activity Drug Design Drug Screening Assays, Antitumor Focused library General aspects Humans Inhibitory Concentration 50 Ketopiperazides Medical sciences Mice Molecular Structure Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Rats Solubility Tubulin - metabolism Tubulin polymerization inhibitor |
| title | Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides |
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