Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma
The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci.2003, 24, 366]. Of the four type 1 PI3Ks, the gamma-isoform, which is expr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (3), p.756-760 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lanni, Jr, Thomas B Greene, Keri L Kolz, Christine N Para, Kimberly S Visnick, Melean Mobley, James L Dudley, David T Baginski, Theodore J Liimatta, Marya B |
| description | The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. Sci.2003, 24, 366]. Of the four type 1 PI3Ks, the gamma-isoform, which is expressed almost exclusively in leukocytes [Curr. Biol., 1997, 7, R470], is of particular interest with respect to its role in inflammatory diseases such as rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) [Mol. Med. Today, 2000, 6, 347]. Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kgamma, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration. |
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Investigation of a series of 4,6-disubstituted-4H-benzo[1,4]oxazin-3-ones has led to the identification of single-digit nanomolar inhibitors of PI3Kgamma, several of which had good cell based activity and were shown to be active in vivo in an aspectic peritonitis model of inflammatory cell migration.</description><identifier>ISSN: 0960-894X</identifier><identifier>PMID: 17095227</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Baculoviridae - drug effects ; Baculoviridae - enzymology ; Class Ib Phosphatidylinositol 3-Kinase ; Drug Design ; Drug Evaluation, Preclinical ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacology ; Escherichia coli - drug effects ; Indicators and Reagents ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - genetics ; Magnetic Resonance Spectroscopy ; Mice ; Mice, Knockout ; Oxazines - chemical synthesis ; Oxazines - pharmacology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007-02, Vol.17 (3), p.756-760</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17095227$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lanni, Jr, Thomas B</creatorcontrib><creatorcontrib>Greene, Keri L</creatorcontrib><creatorcontrib>Kolz, Christine N</creatorcontrib><creatorcontrib>Para, Kimberly S</creatorcontrib><creatorcontrib>Visnick, Melean</creatorcontrib><creatorcontrib>Mobley, James L</creatorcontrib><creatorcontrib>Dudley, David T</creatorcontrib><creatorcontrib>Baginski, Theodore J</creatorcontrib><creatorcontrib>Liimatta, Marya B</creatorcontrib><title>Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The Type 1 PI3Kinases comprise a family of enzymes, which primarily phosphorylate PIP2 to give the second messenger PIP3, a key player in many intracellular signaling processes [Science, 2002, 296, 1655; Trends Pharmacol. 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| ispartof | Bioorganic & medicinal chemistry letters, 2007-02, Vol.17 (3), p.756-760 |
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| subjects | Animals Baculoviridae - drug effects Baculoviridae - enzymology Class Ib Phosphatidylinositol 3-Kinase Drug Design Drug Evaluation, Preclinical Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Escherichia coli - drug effects Indicators and Reagents Isoenzymes - antagonists & inhibitors Isoenzymes - genetics Magnetic Resonance Spectroscopy Mice Mice, Knockout Oxazines - chemical synthesis Oxazines - pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics |
| title | Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma |
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