ABSTRACT
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/genetics , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Cyclin-Dependent Kinase 9/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Protein Kinase Inhibitors/therapeutic use , Receptor, IGF Type 1/genetics , TriageABSTRACT
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Subject(s)
Proline/chemistry , Protein Kinase Inhibitors/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Triazines/chemistry , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Triazines/pharmacologyABSTRACT
A direct, short chiral synthesis of the selective alpha7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Nicotinic Agonists/chemical synthesis , Spiro Compounds/chemical synthesis , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene derivatives are discussed.
Subject(s)
Combinatorial Chemistry Techniques , Furans/chemical synthesis , Hydrocarbons, Fluorinated/chemical synthesis , Oximes/chemistry , Carbazoles/chemistry , Catalysis , Chromatography, High Pressure Liquid , Fluorobenzenes/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Serotonin/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
When hydroboration of 1-octene is carried out in the presence of catalytic amounts of rhodium trichloride followed by the usual oxidation (hydrogen peroxide in aqueous alkali), only minor proportions of 1-octanol (2.4%) are formed accompanied by very significant amounts of 2- (17.4%), 3- (36.9%), and 4-octanol (43.3%). These product compositions are obtained in good overall yield when the borane-THF complex is slowly added to a stirred solution of 1-octene in THF solvent containing the rhodium trichloride. Isomerization of 1-octene to 2-, 3-, and 4-octene in the presence of rhodium trichloride alone is far too slow to account for the foregoing results. The mechanism likely involves multiple and reversible addition/elimination of a Rh-activated B-H species across the double bonds.
