Druglikeness

Basically, it is aU abont balance between risk and certainty. If 11 of the 12 compounds that enter clinical trials are going to fail, it makes sense to find ways to reduce this attrition rate. This message in-honse is no longer new, and more and more outside companies are developing commercial tools to make better predictions for compounds based on the ADMET parameters. The mood inside pharmaceutical companies is serious in taking a close look at compounds in the library that could not be considered druglike and removing them from the file. 

As stated previously, more than 40% of the compounds in clinical trial fail due to poor (bio)pharmaceutical properties (solubility, log P, log D, chemical stability, permeability, metabolism, protein binding, plasma stability, etc.). A lot of efforts are now made to calculate or predict these properties in an early stage of preclinical research to prevent disappointment and the loss of a lot of money farther downstream in the drug discovery process. 

Solubility was probably the most underestimated property of a molecule several years ago. At this moment, however, there is a lot a research to try to predict the solubility of compounds in water, simply because an active componnd has to be dissolved before it can be absorbed. Several methods for predicting aqneons solnbility based on molecular structure have been reported. A significant challenge that remains, however, is the ability to predict solnbility accnrately within a narrower bnt more pharmaceutically relevant range of up to 100 Xg/mL. 

Distribution After the drug has passed through the intestinal wall, it will be distributed by the bloodstream over the human body. Little is know about the uptake of compounds in various organs and tissues, but it is obvious that this will be very important for the efficacy of a compound in the patient. 

Metabolism Also after the uptake in the bloodstream, the drug will face a multitude of metabolizing enzymes in the liver. Several attempts have been made to develop models predictive of metabolic stability. Still a lot of work has to be done in this field. Many in vitro screens have been set up to measure the metabolic stability of compounds in different cell types. 

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Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

Ajay A, Walters WP, Murcko MA. Can we learn to distinguish between druglike and nondrug-like molecules J Med Chem 1998 41 3314-24. 

There are a number of reasons why HTS may not be delivering. Lipinski has argued that compounds coming out of HTS are not druglike [14]. They are too large and too lipophilic. HTS systems by their nature are... 

I. V. In silica approaches to prediction of aqueous and DMSO solubility of druglike compounds trends, problems and solutions. Curr. Med. Chem. 2006, 13, 223-241. 

S. O. Prediction of pH-dependent aqueous solubility of druglike molecules. J. Chem. Inf. Model. 2006, 46, 2601-2609. 

Metabolites are generated by the body s own biochemical processes as a way to facilitate excretion of xenobiotics. The enzymes catalysing in vivo modification of drugs and druglike molecules have a fundamental significance for the pharmaceutical industry. This was once primarily the field of the pharmacologist, but interest in metabolic reactions... 

Frimurer, T.M., Bywater, R., Naerum, L., Lauritsen, L.N., Brunak, S. Improving the odds in discriminating druglike from nondruglike compounds. 

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