Compound properties metabolic stability

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

Recently, much attention has been directed toward the synthesis of peptidomimetics. These compounds can replace native peptides in the interaction with receptors. They showed increased metabolic stability, better bioavailability, and longer duration of action than native peptides, thus displaying favorable pharmacological properties [52-54]. In this sense, the design and synthesis of conformationally restricted peptidomimetics is an important approach toward improving the potency, selectivity, and metabolic stability of peptide based chugs. 

Toxicity is a major cause for the withdrawal of drugs from the market and it is a major concern for pharmaceutical researchers. Reactive metabolism is certainly a very hot topic within the whole approach to drug metabolism. The downstream consequences of not identifying reactive metabolites may be financially catastrophic. There is an increasing drive to have early prediction of the metabolic fate and interactions of candidate drug molecules. Factors such as metabolic stability, toxic metabolite production, and P450 inhibition and induction are all routinely monitored to prevent compounds with poor pharmacokinetic properties from progressing forward onto clinical trials. 

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