Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells
An extensive SAR exploration of the dimethylpyridazin-3( 2H)-one scaffold led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, displaying >100-fold selectivity over the BRCA proficient cells, wi...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1100-1105 |
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| creator | Ferrigno, Federica Branca, Danila Kinzel, Olaf Lillini, Samuele Llauger Bufi, Laura Monteagudo, Edith Muraglia, Ester Rowley, Michael Schultz-Fademrecht, Carsten Toniatti, Carlo Torrisi, Caterina Jones, Philip |
| description | An extensive SAR exploration of the dimethylpyridazin-3(
2H)-one scaffold led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, displaying >100-fold selectivity over the BRCA proficient cells, with clean off-target profiles and low clearance in rats.
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2
H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination. |
| doi_str_mv | 10.1016/j.bmcl.2009.11.087 |
| format | Article |
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2H)-one scaffold led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, displaying >100-fold selectivity over the BRCA proficient cells, with clean off-target profiles and low clearance in rats.
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2
H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.11.087</identifier><identifier>PMID: 20022747</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>6-[4-Fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones ; Animals ; Anticancer agents ; Antineoplastic agents ; Biological and medical sciences ; BRCA1 deficient cancer cells ; BRCA1 Protein - deficiency ; BRCA1 Protein - genetics ; Coupling reactions ; General aspects ; HeLa Cells ; Humans ; Medical sciences ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; PARP-1 inhibitor ; Pharmacokinetic properties ; Pharmacology. Drug treatments ; Piperazines - chemical synthesis ; Piperazines - metabolism ; Piperazines - pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases - metabolism ; Pyridazines - chemical synthesis ; Pyridazines - metabolism ; Pyridazines - pharmacology ; Rats ; SAR exploration</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-02, Vol.20 (3), p.1100-1105</ispartof><rights>2009 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright (c) 2009 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-9ba4f71753a5cfd2e4224957d771c930ed30574e6482230579525e9a7d2a2df63</citedby><cites>FETCH-LOGICAL-c385t-9ba4f71753a5cfd2e4224957d771c930ed30574e6482230579525e9a7d2a2df63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2009.11.087$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22363174$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20022747$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferrigno, Federica</creatorcontrib><creatorcontrib>Branca, Danila</creatorcontrib><creatorcontrib>Kinzel, Olaf</creatorcontrib><creatorcontrib>Lillini, Samuele</creatorcontrib><creatorcontrib>Llauger Bufi, Laura</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Muraglia, Ester</creatorcontrib><creatorcontrib>Rowley, Michael</creatorcontrib><creatorcontrib>Schultz-Fademrecht, Carsten</creatorcontrib><creatorcontrib>Toniatti, Carlo</creatorcontrib><creatorcontrib>Torrisi, Caterina</creatorcontrib><creatorcontrib>Jones, Philip</creatorcontrib><title>Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>An extensive SAR exploration of the dimethylpyridazin-3(
2H)-one scaffold led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, displaying >100-fold selectivity over the BRCA proficient cells, with clean off-target profiles and low clearance in rats.
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2
H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.</description><subject>6-[4-Fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones</subject><subject>Animals</subject><subject>Anticancer agents</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>BRCA1 deficient cancer cells</subject><subject>BRCA1 Protein - deficiency</subject><subject>BRCA1 Protein - genetics</subject><subject>Coupling reactions</subject><subject>General aspects</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>PARP-1 inhibitor</subject><subject>Pharmacokinetic properties</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - metabolism</subject><subject>Piperazines - pharmacology</subject><subject>Poly (ADP-Ribose) Polymerase-1</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Pyridazines - chemical synthesis</subject><subject>Pyridazines - metabolism</subject><subject>Pyridazines - pharmacology</subject><subject>Rats</subject><subject>SAR exploration</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kdGK1DAUhoso7rj6Al5Ib8QZMGOSps0UvBln1RUWHBYFQSSkySmbIW26STrQvdp32IfyPXwS251R77w6h8P3_-dw_iR5TvCSYFK82S2rRtklxbhcErLEK_4gmRFWMJQxnD9MZrgsMFqV7NtJ8iSEHcaEYcYeJyejhFLO-Cz5eQZ7sK5roI2pq9PQVyGa2EfQaYG-M1Tb3nmHMjTvTAde3pgWETRYJX3l2sEuKmhvBvsDsdc50qaBeDXYbvBG36PZnKbnC-RaCKkMaefitKhzdpivz7a_bu-8qVyAxf2oGf0DIJLOt-vLLSKL1LRXpjLR-VGtotnDOEnfXW7WqYbaKDOZKbA2PE0e1dIGeHasp8nXD--_bM7RxeePnzbrC6SyVR5RWUlWc8LzTOaq1hQYpazMueacqDLDoDOccwYFW1E6tWVOcygl11RSXRfZafLq4Nt5d91DiKIxYbpAtuD6IHjGKC_4io0kPZDKuxA81KLzppF-EASLKT-xE1N-YspPECLG_EbRi6N9XzWg_0r-BDYCL4-ADEra2stWmfCPo1mRET5tf3vgYHzG3oAXYfqWAm08qCi0M_-74zfUDrnd</recordid><startdate>20100201</startdate><enddate>20100201</enddate><creator>Ferrigno, Federica</creator><creator>Branca, Danila</creator><creator>Kinzel, Olaf</creator><creator>Lillini, Samuele</creator><creator>Llauger Bufi, Laura</creator><creator>Monteagudo, Edith</creator><creator>Muraglia, Ester</creator><creator>Rowley, Michael</creator><creator>Schultz-Fademrecht, Carsten</creator><creator>Toniatti, Carlo</creator><creator>Torrisi, Caterina</creator><creator>Jones, Philip</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>7X8</scope></search><sort><creationdate>20100201</creationdate><title>Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells</title><author>Ferrigno, Federica ; Branca, Danila ; Kinzel, Olaf ; Lillini, Samuele ; Llauger Bufi, Laura ; Monteagudo, Edith ; Muraglia, Ester ; Rowley, Michael ; Schultz-Fademrecht, Carsten ; Toniatti, Carlo ; Torrisi, Caterina ; Jones, Philip</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-9ba4f71753a5cfd2e4224957d771c930ed30574e6482230579525e9a7d2a2df63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>6-[4-Fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones</topic><topic>Animals</topic><topic>Anticancer agents</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>BRCA1 deficient cancer cells</topic><topic>BRCA1 Protein - deficiency</topic><topic>BRCA1 Protein - genetics</topic><topic>Coupling reactions</topic><topic>General aspects</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>PARP-1 inhibitor</topic><topic>Pharmacokinetic properties</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - metabolism</topic><topic>Piperazines - pharmacology</topic><topic>Poly (ADP-Ribose) Polymerase-1</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Pyridazines - chemical synthesis</topic><topic>Pyridazines - metabolism</topic><topic>Pyridazines - pharmacology</topic><topic>Rats</topic><topic>SAR exploration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferrigno, Federica</creatorcontrib><creatorcontrib>Branca, Danila</creatorcontrib><creatorcontrib>Kinzel, Olaf</creatorcontrib><creatorcontrib>Lillini, Samuele</creatorcontrib><creatorcontrib>Llauger Bufi, Laura</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Muraglia, Ester</creatorcontrib><creatorcontrib>Rowley, Michael</creatorcontrib><creatorcontrib>Schultz-Fademrecht, Carsten</creatorcontrib><creatorcontrib>Toniatti, Carlo</creatorcontrib><creatorcontrib>Torrisi, Caterina</creatorcontrib><creatorcontrib>Jones, Philip</creatorcontrib><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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferrigno, Federica</au><au>Branca, Danila</au><au>Kinzel, Olaf</au><au>Lillini, Samuele</au><au>Llauger Bufi, Laura</au><au>Monteagudo, Edith</au><au>Muraglia, Ester</au><au>Rowley, Michael</au><au>Schultz-Fademrecht, Carsten</au><au>Toniatti, Carlo</au><au>Torrisi, Caterina</au><au>Jones, Philip</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-02-01</date><risdate>2010</risdate><volume>20</volume><issue>3</issue><spage>1100</spage><epage>1105</epage><pages>1100-1105</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>An extensive SAR exploration of the dimethylpyridazin-3(
2H)-one scaffold led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, displaying >100-fold selectivity over the BRCA proficient cells, with clean off-target profiles and low clearance in rats.
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2
H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20022747</pmid><doi>10.1016/j.bmcl.2009.11.087</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry letters, 2010-02, Vol.20 (3), p.1100-1105 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | 6-[4-Fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones Animals Anticancer agents Antineoplastic agents Biological and medical sciences BRCA1 deficient cancer cells BRCA1 Protein - deficiency BRCA1 Protein - genetics Coupling reactions General aspects HeLa Cells Humans Medical sciences Microsomes, Liver - drug effects Microsomes, Liver - enzymology PARP-1 inhibitor Pharmacokinetic properties Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - metabolism Piperazines - pharmacology Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - metabolism Pyridazines - chemical synthesis Pyridazines - metabolism Pyridazines - pharmacology Rats SAR exploration |
| title | Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2 H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells |
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