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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.
4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB.
Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.
- H. Ho, K. Woods, J. Bronson, H. de Boeck, J. C. Martin, M. Hitchcock
- Biology, ChemistryMolecular pharmacology
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.
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.
Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
- W. Kostich, B. Hamman, C. Albright
- BiologyThe Journal of Pharmacology and Experimental…
- 1 September 2016
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.
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.
Biochemical Pharmacology of Acyclic Nucleotide Analogues
- J. Bronson, H. Ho, M. Hitchcock
- Biology, ChemistryAnnals of the New York Academy of Sciences
- 1 December 1990
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.
Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity
- Martin A. Lewis, L. Hunihan, Jeffrey M. Brown
- Biology, ChemistryThe Journal of Pharmacology and Experimental…
- 1 September 2015
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 cognitive…
Discovery of the first antibacterial small molecule inhibitors of MurB.
Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics
Nocathiacin-resistant compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.