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Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors

2012; American Chemical Society; Volume: 55; Issue: 11 Linguagem: Inglês

10.1021/jm300403a

1520-4804

James W. Leahy, Chris A. Buhr, Henry W. B. Johnson, Byung Gyu Kim, TaeGon Baik, Jonah Cannoy, Timothy P. Forsyth, Joon Won Jeong, Matthew Lee, Sunghoon Ma, Kevin Noson, Longcheng Wang, Matthew C. Williams, John M. Nuss, Eric E. Brooks, Paul Foster, Leanne Goon, Nathan Heald, Charles R. Holst, Christopher T. Jaeger, Scott Lam, Julie C. Lougheed, Lam Nguyen, Arthur Plonowski, Joanne Song, Thomas J. Stout, Xiang Wu, Michael Yakes, Peiwen Yu, Wentao Zhang, Peter Lamb, Olivia Raeber,

Mast cells and histamine

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.