Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.

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Lanni TB Jr, Greene KL, Kolz CN, Para KS, Visnick M, Mobley JL, Dudley DT, Baginski TJ, Liimatta MB

Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinasegamma.

Bioorg Med Chem Lett. 2007 Feb 1;17(3):756-60. Epub 2006 Oct 28.

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17095227 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
LY-294002	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	IC 50 (nM)	1720	7.4	30	Details
Wortmannin	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	IC 50 (nM)	19	7.4	30	Details