14395-39-2Relevant academic research and scientific papers
NICOTINIC RECEPTOR COMPOUNDS
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, (2012/03/11)
Provided herein are compounds and methods of preparation of compounds that are capable of functioning as agonists or antagonists of a nicotinic receptor. Also provided are pharmaceutical compositions comprising one or more of these compounds, which may further comprise one or more additional therapeutic agents. Further provided are methods of treatment of various conditions that may be responsive to such activity at the nicotinic receptors, such as nicotine dependence.
Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.
Fraley, Mark E,Rubino, Robert S,Hoffman, William F,Hambaugh, Scott R,Arrington, Kenneth L,Hungate, Randall W,Bilodeau, Mark T,Tebben, Andrew J,Rutledge, Ruth Z,Kendall, Richard L,McFall, Rosemary C,Huckle, William R,Coll, Kathleen E,Thomas, Kenneth A
, p. 3537 - 3541 (2007/10/03)
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5- substituted quinazolinones
Webber,Bleckman,Attard,Deal,Kathardekar,Welsh,Webber,Janson,Matthews,Smith,Freer,Jordan,Bacquet,Howland,Booth,Ward,Hermann,White,Morse,et al.
, p. 733 - 746 (2007/10/02)
The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-resolution ternary crystal complex of Escherichia coli TS, 5'-fluorodeoxyuridylate (5-FdUMP) and a classical glutamate-containing folic acid analog. A preliminary ternary crystal structure of a novel compound was successfully solved. Upon analysis of this initial complex, further structural elaborations were made, and a series of active 5- (arylthio)quinazolinones was developed. The synthetic strategy was based on the displacement of a halogen at the 5-position of a quinazolinone by various arylthioanions. The compounds were tested for inhibition of purified E. coli and/or human TS, and were assayed for cytotoxicity against three tumor cell lines in vitro. Significant thymidine protection effects were observed with several of the inhibitors, indicating that TS was the intracellular locus of activity.
