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Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor.
Compound 4 is a potent inhibitor of γ-secretase, demonstrating a 193-fold selectivity against Notch, and significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. Expand
The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression*
It is shown that the Aβ rise depends on the β-secretase-derived C-terminal fragment of APP (βCTF or C99 levels with low levels with high levels causing rises, while the N-terminally truncated form of Aβ, known as “p3,” formed by α- secretase cleavage, did not exhibit a rise. Expand
4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB.
Activity against the bacterial enzyme MurB supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biological selector. Expand
Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.
The formation and the persistence of H PMPC phosphates in cells and the selective inhibition of viral DNA polymerases by HPMPC diphosphate can explain why cells pretreated with HPM PCs remain refractory to viral infection even long after HPM PC is removed from the medium. Expand
Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity
The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitiveExpand
Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat
Dosages are identified that reduce CSF Aβ levels without causing Notch-related toxicities and demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation ofAvagaceste for AD therapy. Expand
Biochemical Pharmacology of Acyclic Nucleotide Analogues
The results on the effectiveness of infrequent dosing schedules with HPMPC in the treatment of HSV 2 infections in mice support this hypothesis and suggest that inf frequent dosing may be possible due to a prolonged antiviral effect. Expand
Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans. Expand
Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.
A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties. Expand
Discovery of the first antibacterial small molecule inhibitors of MurB.
A series of imidazolinone analogues was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity.