NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses.

Introduction: Currently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease.

Methods: Using amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ-secretase modulator, for the first time in human clinical trials.

Results: Our preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects.

NGP 555, a γ-Secretase Modulator, Lowers the Amyloid Biomarker, Aβ in Cerebrospinal Fluid while Preventing Alzheimer's Disease Cognitive Decline in Rodents.

Introduction: Alzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years.

Methods: Using amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques we investigate the properties of NGP 555, a clinical-stage γ-secretase modulator.

Results: NGP 555 shifts amyloid peptide production to the smaller, non-aggregating forms of amyloid.

Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37).

Respiratory effects of quazepam and pentobarbital.

Quazepam is a new benzodiazepine that may provide good hypnotic action with negligible effect on motor coordination or respiration. Sleep laboratory studies on human volunteers have shown quazepam 15 mg to be an effective hypnotic dose, with the 30-mg dose being optimal. At these doses, there was no deterioration of motor performance, and the drug, when given nightly for two weeks, continued to exert hypnotic effects without serious adverse effects.