Publications by authors named "Russell C Mauger"
Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.
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- - Fragment-based lead generation successfully identified a new series of cyclic amidine inhibitors for beta-secretase (BACE-1), starting with initial compounds that showed millimolar activity through NMR screening.
- - Efforts to improve these fragments involved structure-guided techniques using X-ray crystallography and potency testing, resulting in the development of stronger micromolar inhibitors.
- - Further optimization led to the discovery of dihydroisocytosines, achieving submicromolar potency with Compound 29 being the most promising candidate with an IC50 of 80 nM for future research.
Serine peptidases are a large, well-studied, and medically important class of peptidases. Despite the attention these enzymes have received, details concerning the substrate specificity of even some of the best known enzymes in this class are lacking. One approach to rapidly characterizing substrate specificity for peptidases is the use of positional scanning combinatorial substrate libraries.
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