Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease.

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex.

Small molecules that promote neurogenesis in vitro.

Small molecule modulators of neural stem cell (NSC) differentiation might potentially be developed into orally administered neurogenic drugs to treat neurodegenerative diseases including Alzheimer's disease. New technologies developed for the study of NSC culture, proliferation and differentiation have enabled the establishment of screening platforms to identify small molecules with neurogenic activity. Recent patents claim novel small molecules identified from screening collections that stimulate or otherwise regulate stem cell differentiation and neurogenesis.

Natural products as a robust source of new drugs and drug leads: past successes and present day issues.

The history of drug development has its foundation firmly set in the study of natural remedies used to treat human disease over centuries. Analysis of medicinal plants, bioactive cultures, and increased understanding of micronutrients in the food chain opened the door to the development of purified and defined chemical compounds as dose-controlled medicines. Thus, with the early discovery of cardiotonics in foxglove, salicylic acid in willow bark, morphine in poppies, and penicillin in mold, the pharmaceutical industry was launched.

Molecular diversity in the context of leadlikeness: compound properties that enable effective biochemical screening.

Molecular diversity is of vital importance in drug screening in general and for the discovery and development of new pharmacophores in particular. Biochemical screening is a powerful tool for pharmacophore development given understanding of the properties of a good lead compound operating in the biochemical environment. The properties of leadlikeness have evolved to accommodate the artificial conditions of a biochemical assay.

Failure and success in modern drug discovery: guiding principles in the establishment of high probability of success drug discovery organizations.

The pharmaceutical industry currently suffers unsustainably high program failure rates despite our best efforts to implement drug design methods and to develop high throughput biochemical screening technologies over the past 20 years. While much of this failure is rationalized to be due to uncontrollable late stage drug development issues and clinical events, it has become increasingly clear that the choices we make in early drug discovery are vital to the ultimate failure or success outcomes of our drug discovery programs. The judicious selection of high probability of success therapeutic modalities, the rigorous determination of leadlikeness and druglikeness, and the all-important selection of high probability of success enzyme and receptor targets are the vital drivers of failure and success in small molecule drug discovery as it is performed in the age of biochemical screening.

Computational approaches to the prediction of blood-brain barrier permeability: A comparative analysis of central nervous system drugs versus secretase inhibitors for Alzheimer's disease.

This review summarizes progress made in the development of fully computational approaches to the prediction of blood-brain barrier (BBB) permeability of small molecules, with a focus on rapid computational methods suitable for the analysis of large compound sets and virtual screening. A comparative analysis using the recently developed Advanced Chemistry Development (ACD/Labs) Inc BBB permeability algorithm for the calculation of logBB values for known Alzheimer's disease medicines, selected central nervous system drugs and new secretase inhibitors for Alzheimer's disease, is presented. The trends in logBB values and the associated physiochemical properties of these agents as they relate to the potential for BBB permeability are also discussed.

Nonleadlikeness and leadlikeness in biochemical screening.

Biochemical assays have largely supplanted functional biological assays as drug screening tools in the early stages of drug discovery. The de-selection of compounds that are 'nonleadlike' binders (and bonders) and the proactive selection of those compounds that are 'leadlike' in their binding to the target are vital components of the screening effort. The physiochemical properties of leadlikeness and the surprising differences between those properties and the now classical definitions of druglikeness are becoming apparent.