Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors.

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.

Discovery of a novel series of Notch-sparing gamma-secretase inhibitors.

Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.

Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors.

Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.

Brain and plasma exposure profiling in early drug discovery using cassette administration and fast liquid chromatography-tandem mass spectrometry.

A method using reverse phase liquid chromatography-tandem mass spectrometry and cassette administration was developed for in vivo brain and plasma exposure profiling to assist early CNS drug discovery programs. Three to four compounds were grouped in cassettes for dosing and analysis. Compounds in the cassettes were selected to minimize possible analytical interference from each other, as well as from their potential metabolites. In order to improve the confidence of cassette administration, an analogue of the study compounds, with well-established brain penetration data, was included in each cassette as a "biological internal standard". Compounds were administered to rats by intraperitoneal injection and extracted from plasma or brain homogenate by simple protein precipitation. Fast chromatographic separation was achieved by using a short narrow-bore column at a flow rate of 1.0ml/min with a fast gradient. The brain penetration of the compounds was evaluated by comparing their C(max) and AUC values in brain and plasma. This approach rapidly provided early brain penetration and plasma exposure information, thus making more of this data available to teams. Comparing the brain exposures to the EC(50) values (i.e. in vitro potency) of series compounds in the same discovery program provided another dimension of information to select lead compounds for future in vivo assessment. The method described here has been used for providing early brain penetration information in several CNS exploratory and discovery programs.