title: Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR.
abstract: 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.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.kendall@auckland.ac.nz
authors.forename: Jackie D
authors.initials: JD
authors.lastname: Kendall
authors.forename: Anna C
authors.initials: AC
authors.lastname: Giddens
authors.forename: Kit Yee
authors.initials: KY
authors.lastname: Tsang
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Marshall
authors.forename: Ripudaman
authors.initials: R
authors.lastname: Singh
authors.forename: Claire L
authors.initials: CL
authors.lastname: Lill
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Lee
authors.forename: Sharada
authors.initials: S
authors.lastname: Kolekar
authors.forename: Mindy
authors.initials: M
authors.lastname: Chao
authors.forename: Alisha
authors.initials: A
authors.lastname: Malik
authors.forename: Shuqiao
authors.initials: S
authors.lastname: Yu
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.forename: Christina
authors.initials: C
authors.lastname: Buchanan
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Stephen M F
authors.initials: SM
authors.lastname: Jamieson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; C023666:pyridine