Christopher Lipinski - Drug-like properties and the causes of poor solubility and poor permeability.

Document created by Christopher Lipinski on Aug 22, 2014
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  Publication Details (including relevant citation   information): Lipinski, C. A., Journal of   pharmacological and toxicological methods,   2000, 44 (1), pp 235-249

  Abstract: There are currently about 10000   drug-like compounds. These are sparsely, rather than uniformly,   distributed through chemistry space. True diversity does not   exist in experimental combinatorial chemistry screening   libraries. Absorption, distribution, metabolism, and excretion   (ADME) and chemical reactivity-related toxicity is low, while   biological receptor activity is higher dimensional in chemistry   space, and this is partly explainable by evolutionary pressures   on ADME to deal with endobiotics and exobiotics. ADME is hard to   predict for large data sets because current ADME experimental   screens are multi-mechanisms, and predictions get worse as more   data accumulates. Currently, screening for biological receptor   activity precedes or is concurrent with screening for properties   related to "drugability." In the future, "drugability" screening   may precede biological receptor activity screening. The level of   permeability or solubility needed for oral absorption is related   to potency. The relative importance of poor solubility and poor   permeability towards the problem of poor oral absorption depends   on the research approach used for lead generation. A "rational   drug design" approach as exemplified by Merck advanced clinical   candidates leads to time-dependent higher molecular weight,   higher H-bonding properties, unchanged lipophilicity, and, hence,   poorer permeability. A high throughput screening (HTS)-based   approach as exemplified by unpublished data on Pfizer (Groton,   CT) early candidates leads to higher molecular weight, unchanged   H-bonding properties, higher lipophilicity, and, hence, poorer   aqueous solubility.

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