TY - JOUR
T1 - Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors
T2 - Exploring the benzenesulfonohydrazide SAR
AU - Kendall, J.D.
AU - Giddens, A.C.
AU - Tsang, K.Y.
AU - Frédérick, R.
AU - Marshall, E.S.
AU - Singh, R.
AU - Rewcastle, G.W.
AU - Baguley, B.C.
AU - Flanagan, J.U.
AU - Jamieson, S.M.F.
AU - Denny, W.A.
AU - Chaussade, C.
AU - Buchanan, C.
AU - Shepherd, P.R.
AU - Lill, C.L.
AU - Lee, W.-J.
AU - Kolekar, S.
AU - Chao, M.
AU - Malik, A.
AU - Yu, S.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84855202236&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.11.031
DO - 10.1016/j.bmc.2011.11.031
M3 - Article
AN - SCOPUS:84855202236
SN - 0968-0896
VL - 20
SP - 58
EP - 68
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 1
ER -