Blood-brain barrier discovery

Hou, T. J., Xu, X. J. ADME evaluation in drug discovery. 3. Modeling blood-brain barrier partitioning using simple molecular descriptors. /. Chem. Inf. Model. 2003, 43, 2137-2152. 

Cecchelli, R, Berezowski, V, Lundquist, S, Culot, M, Renftel, M, Dehouck, MP, and Fenart, L, 2007. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov 6, 650-661. 

Hou TJ, Xu XJ (2003) ADME Evaluation in Drug Discovery. 3. Modeling Blood-Brain Barrier Partitioning Using Simple Molecular Descriptors. Erratum in J Chem Inf Comput Sci. 2004 Mar-Apr 44(2) 766-70. J Chem Inf Comput Sci 43 2137-2152. 

Liu R, Sun H, So SS (2001) Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration. J Chem Inf Comput Sci 41 1623-1632. 

There are several efflux pumps which may affect absorption, blood-brain-barrier penetration, and reabsorption from kidney microtubules. The most commonly tested efflux pump in early drug discovery is the P-glycoprotein. Assays to identify P-glycoprotein substrates or inhibitors can be run using a variety of cell lines. 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

The use of in vitro cell culture models for mechanistic studies and as permeability screens for the blood-brain barrier in the pharmaceutical Industry-Background and current status in the drug discovery process. Vascular Pharmacology, 38, 355-364. 

The discovery that dopamine was depleted in the basal ganglia of patients who suffered from Parkinsonism at the time of death led to the rational development of the therapeutic treatment, namely the use of L-dopa. Since dopamine does not cross the blood-brain barrier, and is rapidly catabolized... 

Immunosuppressants, such as FK506, repamycinans cyclosporine A (CsA), attracted intensive research interests during the late 1980s and early 1990s,3233 with the aim to understand the mechanism of action.34 Renewed interest in these compounds developed from the discovery that some of the compounds, such as FKBP-12, have the potential to penetrate the blood-brain barrier and have also demonstrated a capacity for nerve regeneration activity. 

Clark DE, Pickett SD (2000) Computational methods for the prediction of drug-likeness . Drug Disc Today 5 49-58 Clark DE (2001) Prediction of intestinal absorption and blood-brain barrier penetration by computational methods. Comb Chem High Throughput Screen 4 477-496 Drews J (2000) Drug discovery a historical perspective. Science 287 1960-1964... 

The discovery that the neutral, lipophilic 99mTcO complex 36, prepared by the reduction of Tc04 in the presence of the tetradentate propyleneamine oxime ligand, is able to cross the blood-brain barrier in both directions has stimulated much work in this area (19). 

VolSurfwas initially validated on oral absorption [16, 17] and blood-brain-barrier permeation [18] models (see belovi ). VolSurf has continued to be developed to improve in silico predictions for ADME properties, although its use has also been extended to receptor-based evaluation of binding affinity [19, 20], While other soft-ivare tools for ADME modeling are available (see, e.g., [21]), the MIF-based collection of sofhvare and models available from Molecular Discovery (MD) is both extensive and ivell validated by the private sector. Three programs from MD, VolSurf, MetaSite and Almond, are particularly suited for rapid evaluation of large compound sets [22] in connection ivith ADME/Tox related properties ... 

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