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 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.
Lanni
Thomas B
TB
Chemistry Department, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Thomas.Lanni@pfizer.com
Greene
Keri L
KL
Kolz
Christine N
CN
Para
Kimberly S
KS
Visnick
Melean
M
Mobley
James L
JL
Dudley
David T
DT
Baginski
Theodore J
TJ
Liimatta
Marya B
MB
D000818:Animals; D016367:Baculoviridae / Q000187:drug effects / Q000201:enzymology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors
D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D010078:Oxazines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546764:Pik3cg protein, mouse