Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR

J.D. Kendall, A.C. Giddens, K.Y. Tsang, R. Frédérick, E.S. Marshall, R. Singh, G.W. Rewcastle, B.C. Baguley, J.U. Flanagan, S.M.F. Jamieson, W.A. Denny, C. Chaussade, C. Buchanan, P.R. Shepherd, C.L. Lill, W.-J. Lee, S. Kolekar, M. Chao, A. Malik, S. Yu

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Résumé

Structure-activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110α selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues.
langue originaleAnglais
Pages (de - à)58-68
Nombre de pages11
journalBioorganic and Medicinal Chemistry
Volume20
Numéro de publication1
Les DOIs
Etat de la publicationPublié - 1 janv. 2012

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