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 Aß oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aß oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aß oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer's disease.

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. Several patents claim newly discovered NSC differentiation modulating activity of previously marketed drugs suggesting perhaps a previously unknown mechanism of action of these drugs and/or implicating the target enzyme and receptor pathways as key players in neurogenesis. This relatively new area of research into small molecule modulators of neurogenesis is reviewed and recent patents claiming small molecule neurogenic compounds, potentially orally administered CNS regenerative therapies are summarized.

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. Such natural small molecules served as treatments for disease and ultimately, as pharmacologic tools to enable the understanding of the biochemical pathways and mechanisms of disease. In contrast, modern drug discovery technologies coupled with the powerful tools of biotechnology have prompted drug discovery organizations to focus on target-driven drug discovery at the molecular level by launching high-throughput screening programs using artificial biochemical assays. At a time when the pharmaceutical industry has come under scrutiny for high rates of drug development failure, it is interesting to see that natural products drug discovery has been marginalized in favor of this high-throughput biochemical screening paradigm. If modern drug development is once again to benefit from natural products as a source, then the limitations of artificial biochemical assays as applied to the screening of natural extracts must be realized in order to capitalize on the vast natural molecular diversity and rich ethnobotanic data that has emerged worldwide. Natural compounds can again become central players in the treatment of disease and in the understanding of disease mechanisms.

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. Accordingly, the properties of leadlikeness that are suited for screening at protein targets biochemically are different and complementary to the properties of druglikeness used to guide the selection of good compounds studied biologically in cellular studies and animal models. The benefits of leadlikeness in the biochemical screening arena (including fragment-based screening and co-crystallization studies) are described here and recommendations are forwarded for the generation of leadlike molecular diversity. Chemically stable low molecular weight 'minimalist' compounds (or fragments) with dense heteroatom substitution and variable conformational constraint are promoted as conceptually superior compounds for 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.

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. Consideration of these guiding principles will improve our chances of success in drug discovery, and increase our ability to address unmet medical need in the future.

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.