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Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466
The pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD) and highlight a previously undescribed role for 5- HT6 receptors to modulate basal GABA and stimulated glutamate transmission. Expand
Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.
Three pyrazolopyrimidine ATP-competitive mTOR inhibitors are reported, with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold), to highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTORKinase inhibitors as new cancer therapy. Expand
Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated alpha-linked acidic dipeptidase.
Inhibition of NAALADase may show utility as a therapeutic intervention in diseases in which altered levels of glutamate are thought to be involved, and is suggested to act as a storage form of synaptic glutamate. Expand
Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists.
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists havingExpand
Identification of a new class of small molecule C5a receptor antagonists.
The lead compounds in this series are selective and block C 5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency. Expand
Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
Side chain modification afforded the potent Notch-1-sparing GSI begacestat, selected for development for the treatment of Alzheimer's disease, which had improved in vivo potency. Expand
Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist.
Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders. Expand
Identification and characterization of acidic mammalian chitinase inhibitors.
Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments and revealed that the larger more potent HTS hits spanned from the active site pocket to a hydrophobic pocket. Expand
Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors.
X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Expand