ABSTRACT
We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.
Subject(s)
Antineoplastic Agents/pharmacology , Fibroblast Growth Factors/metabolism , Protein Kinase Inhibitors/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Receptors, Fibroblast Growth Factor/genetics , Signal Transduction/drug effects , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step "catch and release" protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration. A 48-member sulfonamide library was prepared as two 24-member sublibraries, affording library compounds in good yields and high purities without the need for further column chromatographic purification.
Subject(s)
Combinatorial Chemistry Techniques/methods , Sulfonamides/chemical synthesis , Combinatorial Chemistry Techniques/instrumentation , Molecular Structure , Sulfonamides/chemistry , Time FactorsABSTRACT
A multistep, polymer-assisted solution phase strategy for the highly automated (auto-PASP) synthesis of 2-alkylthiobenzimidazole and N,N'-dialkylbenzimidazolin-2-one libraries is presented. The approach incorporates in-line purification techniques to afford library products directly with high purities and is exemplified by the preparation of a 96-member 2-alkylthiobenzimidazoline library 1[1-12,1-8] and a 72-member N,N'-dialkylbenzimidazolin-2-one library 9[1-12,1-6].
ABSTRACT
The polymer-assisted solution-phase (PASP) synthesis of a 192-member 2-D array of 1,5-biaryl pyrazoles 4[1-12,1-16] is reported. The synthesis was performed in a fully automated manner using a multiprobe top-filtration robot and incorporates a "catch and release" step to afford library compounds directly in high yield and purity.
Subject(s)
Combinatorial Chemistry Techniques , Pyrazoles , Catalysis , Molecular Structure , Organic Chemicals , Polymers , SolutionsABSTRACT
The polymer-assisted solution phase synthesis (PASP) of an array of histone deacetylase (HDAc) inhibitors is described. HDAc inhibitors have considerable potential as new anti-proliferative agents. Selected compounds were shown to inhibit both human endothelial cell proliferation, and the formation of tubules (neovascularisation) in an in vitro model of angiogenesis.
Subject(s)
Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Polymers/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Humans , Molecular Structure , Neovascularization, Pathologic/pathologyABSTRACT
The first fully automated multi-step polymer assisted solution phase (PASP) synthesis is described. An array of histone deacetylase (HDAc) inhibitors was prepared by an unattended 4-5 step sequence incorporating in-line 'catch and release' purification.
