1. Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.
- Author
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Leahy JW, Buhr CA, Johnson HW, Kim BG, Baik T, Cannoy J, Forsyth TP, Jeong JW, Lee MS, Ma S, Noson K, Wang L, Williams M, Nuss JM, Brooks E, Foster P, Goon L, Heald N, Holst C, Jaeger C, Lam S, Lougheed J, Nguyen L, Plonowski A, Song J, Stout T, Wu X, Yakes MF, Yu P, Zhang W, Lamb P, and Raeber O
- Subjects
- Administration, Oral, Animals, Biological Availability, Cell Line, Crystallography, X-Ray, Female, High-Throughput Screening Assays, Humans, Isoenzymes antagonists & inhibitors, Luminescent Measurements, Mice, Microsomes, Liver metabolism, Models, Molecular, Molecular Structure, Phosphorylation, Piperazines pharmacokinetics, Piperazines pharmacology, Proto-Oncogene Proteins c-akt metabolism, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Sulfones pharmacokinetics, Sulfones pharmacology, Phosphoinositide-3 Kinase Inhibitors, Piperazines chemical synthesis, Sulfonamides chemical synthesis, Sulfones chemical synthesis
- Abstract
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.
- Published
- 2012
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