Cassette Dosing Approach and Quantitative Structure-Pharmacokinetic Relationship Study of Antifungal N-Myristoyltransferase Inhibitors

Pharmacokinetic (PK) parameters of N-myristoyltransferase (Nmt) inhibitors were measured, and a multivariate quantitative structure-pharmacokinetic relationship (QSPKR) model for predicting rat elimination half-life (t(1/2)) values was constructed. One hundred seven benzofuran derivatives have been selected as the data set for QSPKR analysis. The correlation between the t(1/2) values and 30 physicochemical descriptors was examined by a stepwise multiple linear regression method. The statistical analysis gives a significant QSPKR model (r = 0.843) with the following three variables: partial negative surface area (PNSA), atomic-based octanol/water partition coefficient (AlogP), and the number of rotational bonds (Rotlbonds). The QSPKR model obtained is predictive and simple, and would give a direction for designing new Nmt inhibitors having good PK profiles.

[1]  K. Adkison,et al.  Simultaneous pharmacokinetic screening of a mixture of compounds in the dog using API LC/MS/MS analysis for increased throughput. , 1997, Journal of medicinal chemistry.

[2]  H. van de Waterbeemd,et al.  Development of quantitative structure-pharmacokinetic relationships. , 1985, Environmental health perspectives.

[3]  Evans,et al.  Approaches to higher-throughput pharmacokinetics (HTPK) in drug discovery. , 2000, Drug discovery today.

[4]  W. Shelver,et al.  Quantitative structure-pharmacokinetic relationships (QSPR) of beta blockers derived using neural networks. , 1995, Journal of pharmaceutical sciences.

[5]  H. van de Waterbeemd,et al.  Property-based design: optimization of drug absorption and pharmacokinetics. , 2001, Journal of medicinal chemistry.

[6]  Walter A. Korfmacher,et al.  Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats , 1999 .

[7]  P. Veng‐Pedersen,et al.  Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not confined to a congeneric series. , 1994, Journal of pharmaceutical sciences.

[8]  C. Hop,et al.  Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. , 1998, Journal of pharmaceutical sciences.

[9]  K. Adkison,et al.  Use of "N-in-One" dosing to create an in vivo pharmacokinetics database for use in developing structure-pharmacokinetic relationships. , 1999, Journal of pharmaceutical sciences.

[10]  S. Toon,et al.  Structure-pharmacokinetic relationships among the barbiturates in the rat. , 1983, The Journal of pharmacology and experimental therapeutics.

[11]  Sample pooling to enhance throughput of brain penetration study. , 1999, Journal of pharmaceutical and biomedical analysis.

[12]  W. Day,et al.  Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application , 2004, Pharmaceutical Research.

[13]  O. Wassermann,et al.  Quantitative structure-pharmacokinetic relationships derived on antibacterial sulfonamides in rats and its comparison to quantitative structure-activity relationships. , 1980, Journal of medicinal chemistry.

[14]  P. Woster,et al.  Terminally alkylated polyamine analogues as chemotherapeutic agents. , 2001, Journal of medicinal chemistry.

[15]  K. Kawasaki,et al.  Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1. , 2001, Bioorganic & medicinal chemistry letters.

[16]  P. Woollard,et al.  Cassette dosing: rapid in vivo assessment of pharmacokinetics , 1998 .

[17]  F. Beaudry,et al.  In vivo pharmacokinetic screening in cassette dosing experiments; the use of on-line Pprospekt liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry technology in drug discovery. , 1998, Rapid communications in mass spectrometry : RCM.

[18]  M Danhof,et al.  Multivariate quantitative structure-pharmacokinetic relationships (QSPKR) analysis of adenosine A1 receptor agonists in rat. , 1999, Journal of pharmaceutical sciences.

[19]  M H Tarbit,et al.  High-throughput approaches for evaluating absorption, distribution, metabolism and excretion properties of lead compounds. , 1998, Current opinion in chemical biology.

[20]  T. Olah,et al.  The simultaneous determination of mixtures of drug candidates by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry as an in vivo drug screening procedure. , 1997, Rapid communications in mass spectrometry : RCM.