Drug development pharmacokinetics

Lead structure According to Valler and Green s definition a lead structure is a representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development program [12]. 

Pharmacokinetic and Pharmacodynamic Aspects of Drug Development of Agents for... 

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. 

Sheiner LB, Steimer JL. Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 2000 40 67-95. 

Rowland M, Balant L, Peck C. Physiologically based pharmacokinetics in drug development and regulatory science a workshop report (Georgetown University, Washington, DC, May 29-30, 2002). AAPS PharmSci 2004 6 E6. 

Charnick SB, Kawai R, Nedelman JR, Lemaire M, Niederberger W, Sato H. Perspectives in pharmacokinetics. Physiologically based pharmacokinetic modeling as atoolfor drug development./P/jarmacokmefTEop/jarm 1995 Apr 23(2) 217-29. Review. 

Theil FP, Guentert TW, Haddad S, Poulin P. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 2003 Feb 18 138(l-2) 29-49. Review. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

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... 

It is only during the past few years that the importance of the metabolic and pharmacokinetic behavior of drug molecules in the drug discovery process has been recognized. One of the causes for failure in drug development is the lack of suitable pharmacokinetic properties of drug candidates. At the same time, the development... 

Sinko, P. J., Drug selection in early drug development screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches, Curr. Opin. Drug Disc. Dev. 1999, 2, 42-48. 

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