ADMET profile

In particular, in silico methods are expected to speed up the drug discovery process, to provide a quicker and cheaper alternative to in vitro tests, and to reduce the number of compounds with unfavorable pharmacological properties at an early stage of drug development. Bad ADMET profiles are a reason for attrition of new drug candidates during the development process [9, 10]. The major reasons for attrition of new drugs are ... 

Prediction of various physicochemical properties such as solubihty, lipophhicity log P, pfQ, number of H-donor and acceptor atoms, number of rotatable bonds, polar surface area), drug-likeness, lead-likeness, and pharmacokinetic properties (ADMET profile). These properties can be applied as a filter in the prescreening step in virtual screening. 

Other filters used for prefiltering account for lead- [22, 23] or drug-likeness [24-26], an appropriate ADMET profile [27-30], or favorable properties concerning receptor binding [31, 32]. 

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

More recently the concept of ADMET profile (Absorption Distribution Metabolism Excretion Toxicity profile) has further streamlined the molecular pharmacology aspects of these drugs with the ultimate objective of providing efficient target directed drugs with least toxicity. 

Sorafenib (l)11 is a multikinase inhibitor marketed by Bayer and Onyx. Sorafenib blocks tyrosine kinases as well as serine/threonine kinases. Its story began in 1994 when Bayer and Onyx entered a collaboration to discover novel Raf/MEK/ERK inhibitors. They first discovered a very mildly active compound 8 (/C50 17 pM) against Rafl kinase in 1995 from screening a collection of 200,000 compounds. The optimization of its potency and its ADMET profile using medicinal chemistry and combinatorial chemistry methods led to the identification of sorafenib (1) in 1999 as a preclinical development candidate. Multiple phase I studies started in 2000, when sorafenib tosylate (19) was evaluated in patents with advanced solid tumors of different types. In December 2005, Sorafenib tosylate (19) received U.S. FDA approval for the treatment of advanced renal cell carcinoma (RCC). Two years later, it was approved for the treatment of unresectable hepatocellular carcinoma (HCC). 

The profiles of compounds (30) and (34) are shown in Table 1. As can be seen in the above table, the potency (biochemical and cellular) of keto acid 30 is superior to the sulfonamide 34. However, due to difficulties with solubility and detection of the compound in LC/MS, the full ADMET profile could not be gathered for compound 30. Compound 34 although more readily profiled in the ADMET assays was shown to have several liabilities, including microsome instability, inhibition of... 

Integrated systems suitable for processing the sometimes quite complex workflows more easily or automatically and to optimize new compounds in parallel for their potency, selectivity, and ADMET profile have to be developed. The reliability of the in silico models will be improved and their scope for predictions will be broader as soon as more reliable experimental data are available. However, there is the paradox of predictivity versus diversity. The greater the chemical diversity in a dataset. 

Shou, W.Z., Zhang, J. (2006) Recent development in high-throughput bioanalytical support for in vitro ADMET profiling. Expert Opin. Drug Metab. Toxicol., 6(3), 321-336. 

ECso = 3.7nM) demonstrated balanced potency and pharmacokinetic (absorption, distribution, metabolism, excretion, toxicity (ADMET)) profiles. In addition, compound 73 exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model. 

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