As part of our investigation into the pyrazolo[1,5-a]pyridines as novel PI3K inhibitors, we report a range of analogues where the central linker portion of the molecule was varied while retaining the pyrazolo[1,5-a] pyridine and arylsulfonyl or arylcarbonyl groups. Isostere generating software BROOD was used to assist with producing ideas. The isoform selectivity of the compounds varied from pan-PI3K for compound 41 to p110a-selective for compound 58 or p110d-selective for compound 57. The latter two compounds varied only in their sulphur oxidation state.
Shuttleworth Stephen, Silva Franck, Tomassi Cyrille, Cecil Alexander, Hill Thomas, Rogers Helen, Townsend Paul, Progress in the Design and Development of Phosphoinositide 3-Kinase (PI3K) Inhibitors for the Treatment of Chronic Diseases, Progress in Medicinal Chemistry (2009) ISBN:9780444533586 p.81-131, 10.1016/s0079-6468(09)04803-6
Hollander M. Christine, Blumenthal Gideon M., Dennis Phillip A., PTEN loss in the continuum of common cancers, rare syndromes and mouse models, 10.1038/nrc3037
Chaussade Claire, Cho Kitty, Mawson Claire, Rewcastle Gordon W., Shepherd Peter R., Functional differences between two classes of oncogenic mutation in the PIK3CA gene, 10.1016/j.bbrc.2009.02.081
Cleary James M., Shapiro Geoffrey I., Development of Phosphoinositide-3 Kinase Pathway Inhibitors for Advanced Cancer, 10.1007/s11912-010-0091-6
Liu Pixu, Cheng Hailing, Roberts Thomas M., Zhao Jean J., Targeting the phosphoinositide 3-kinase pathway in cancer, 10.1038/nrd2926
Jamieson Stephen, Flanagan Jack U., Kolekar Sharada, Buchanan Christina, Kendall Jackie D., Lee Woo-Jeong, Rewcastle Gordon W., Denny William A., Singh Ripudaman, Dickson James, Baguley Bruce C., Shepherd Peter R., A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types, 10.1042/bj20110502
Wu Peng, Hu Yongzhou, Small molecules targeting phosphoinositide 3-kinases, 10.1039/c2md20044a
Markman Ben, J. Tao Jessica, Scaltriti Maurizio, PI3K Pathway Inhibitors: Better Not Left Alone, 10.2174/138161213804547213
Kendall Jackie D., O’Connor Patrick D., Marshall Andrew J., Frédérick Raphaël, Marshall Elaine S., Lill Claire L., Lee Woo-Jeong, Kolekar Sharada, Chao Mindy, Malik Alisha, Yu Shuqiao, Chaussade Claire, Buchanan Christina, Rewcastle Gordon W., Baguley Bruce C., Flanagan Jack U., Jamieson Stephen M.F., Denny William A., Shepherd Peter R., Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors, 10.1016/j.bmc.2011.11.029
Kendall Jackie D., Giddens Anna C., Tsang Kit Yee, Frédérick Raphaël, Marshall Elaine S., Singh Ripudaman, Lill Claire L., Lee Woo-Jeong, Kolekar Sharada, Chao Mindy, Malik Alisha, Yu Shuqiao, Chaussade Claire, Buchanan Christina, Rewcastle Gordon W., Baguley Bruce C., Flanagan Jack U., Jamieson Stephen M.F., Denny William A., Shepherd Peter R., Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR, 10.1016/j.bmc.2011.11.031
Nelson Sidney D., Metabolic activation and drug toxicity, 10.1021/jm00349a001
Berndt Alex, Miller Simon, Williams Olusegun, Le Daniel D, Houseman Benjamin T, Pacold Joseph I, Gorrec Fabrice, Hon Wai-Ching, Liu Yi, Rommel Christian, Gaillard Pascale, Rückle Thomas, Schwarz Matthias K, Shokat Kevan M, Shaw Jeffrey P, Williams Roger L, The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors, 10.1038/nchembio.293
Lipinski Christopher A., Lombardo Franco, Dominy Beryl W., Feeney Paul J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, 10.1016/s0169-409x(96)00423-1
Kaboudin Babak, Elhamifar Dawood, Phosphorus Pentasulfide: A Mild and Versatile Reagent for the Preparation of Thioamides from Nitriles, 10.1055/s-2005-918507
Yokoyama Masataka, Hatanaka Hidekatsu, Preparative Methods for Dialkyl Dithioseleno- and Thiodiselenocarbonates, 10.1055/s-1985-31374
Rasmussen C. R., Villani, Jr. F. J., Weaner L. E., Reynolds B. E., Hood A. R., Hecker L. R., Nortey S. O., Hanslin A., Costanzo M. J., Powell E. T., Molinari A. J., Improved Procedures for the Preparation of Cycloalkyl-, Arylalkyl-, and Arylthioureas, 10.1055/s-1988-27605
Mahboobi Siavosh, Dove Stefan, Sellmer Andreas, Winkler Matthias, Eichhorn Emerich, Pongratz Herwig, Ciossek Thomas, Baer Thomas, Maier Thomas, Beckers Thomas, Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-Type and Mutant BCR-ABL, PDGF-Rβ, and Histone Deacetylases†, 10.1021/jm800988r
Prokopcová Hana, Kappe C. Oliver, Palladium(0)-Catalyzed, Copper(I)-Mediated Coupling of Boronic Acids with Cyclic Thioamides. Selective Carbon−Carbon Bond Formation for the Functionalization of Heterocycles†, 10.1021/jo070408f
Chaussade Claire, Rewcastle Gordon W., Kendall Jackie D., Denny William A., Cho Kitty, Grønning Line M., Chong Mei Ling, Anagnostou Sasha H., Jackson Shaun P., Daniele Nathalie, Shepherd Peter R., Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling, 10.1042/bj20070003
Bibliographic reference
Kendall, Jackie D. ; Marshall, Andrew J. ; Giddens, Anna C. ; Tsang, Kit Yee ; Boyd, Maruta ; et. al. Novel pyrazolo[1,5-a]pyridines as PI3K inhibitors: variation of the central linker group. In: MedChemComm, Vol. 5, no.1, p. 41 [1-6] (2014)