Metabolism metabolic stability

Metabolism Metabolic stability (see Section 6.3.2.1) Metabolic soft-spot identification (see Table 6.10) Reactive metabolites (see Table 6.10) Assessing in vitro metabolic liabilities by drug-metabohsm enzymes such as CYP Predicting in vivo clearance Assay ° Liver microsomes from various species ° NADPH as co-factor ° 0.5-5 i,M incubation concentration Analysis ° PPT followed by LC-MS/MS or onhne SPE-MS/MS... 

An ideal" drug must be safe and effective. The mavimum daily dose should not exceed 200-300 mg. Drugs should be well absorbed orally and bioavailablc. Metabolic stability ensures a reasonable long half-life. Further on, a drug should be non-... 

Shen M, Xiao Y, Golbraikh A, Gombar VK, Tropsha A. Development and validation of k-nearest-neighbor QSPR models of metabolic stability of drug candidates. J Med Chem 2003 46 3013-20. 

Bnrsi R, de Gooyer ME, Grootenhuis A, Jacobs PL, van der Louw J, Leysen D. (Q)SAR stndy on the metabolic stability of steroidal androgens. J Mol Graph Modelling 2001 19 552-6. 

When assayed in HEK293 cells transfected with the cloned human, rat and guinea pig TRPVl, (23a) showed similar potencies. Not unexpeetedly, (23a) showed poor metabolic stability and a structure-activity study to optimize potency and drug-like properties was initiated. Modification on the left-handed A -aryl section showed that ... 

Drug candidates that are intended for oral dosing need to have good ADME properties so that they can be dosed once or twice daily. The drug should be well absorbed, survive first pass metabolism, and have sufficiently low clearance. At the lead identification stage, the primary in vitro ADME assays employed are those that assess permeability and metabolic stability. There are a variety of assays available for both parameters, as described in the previous chapter. 

Abadji Y, Lin SY, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makri-yannis A. (R)-Methanandamide a chiral novel anandamide possessing higher potency and metabolic stability. J Med Chem 1994 37 1889-1893. 

Goutopoulos A, Fan P, Khanolkar AD, Xie XQ, Lin SY, Makriyannis A. Stereochemical selectivity of methanandamides for the CB1 and CB2 cannabinoid receptors and their metabolic stability. Bioorg Med Chem 2001 9 1673-1684. 

Biological activity is not the only criterion required for drug development, as anyone who has been involved in this area is aware. Potency, toxicity, bioavailability, metabolic stability, and plasma half-life are only a few of the critical issues that must be addressed. Although satisfactory potency and spectrum activity had been achieved with WIN54954, which has been clinically evaluated, this compound lacked metabolic stability and consequently displayed a short half-life. 

The question at this point was whether modifications could be made to the oxadiazole molecule to enhance metabolic stability and achieve comparable activity. This approach required knowledge of the site of metabolism and the nature of the metabolic products. This information was obtained from ion mass spectrometry. The identity of these products was determined by comparing the fragmentation pattern of metabolites A and B with the parent compound and the corresponding daughter ions (Fig. 25). 

Kauffman, S. (1969) Metabolic stability and epigenesis in randomly constructed genetic nets. /. Theoret. Biol., 22 437-467, Elsevier, Amsterdam. 

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... 

Kubiak, T.M., Maule, A.G., Marks, N.J., Martin, R.A. and Weist, J.R. (1996) Importance of the proline residue to the functional activity and metabolic stability of the nematode FMRFamide-related peptide, KPNFIRFamide (PF4). Peptides 17, 1267-1277. 

Mandagere, A. K., T. N. Thompson, and K. K. Hwang. Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates, J. Med. Chem. 2002, 45, 304-311... 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

Metabolic stability in human liver preparations may represent a suitable experimental tool to obtain relevant pharmacokinetic information in an early phase of drug discovery. Compounds which are metabolized principally by the liver can be identified and studied in more detail to determine the principal sites of biotransformation. 

The aim of the present example was to investigate whether the assessment of an in silico model of metabolic stability from a training set of several hundred drugs or drug-like compounds in human CYP3A4 cDNA-expressed microsomal preparations, would offer a suitable approach to predict the metabolic stability of external compounds. 

A simple protocol was used to build the compounds compounds were modeled with the corresponding net charges, after which 2D-3D structure conversion was carried out using the program Concord [21]. The 3D dataset obtained was submitted to the VolSurf program, and principal component analysis (PCA) was applied for chemometric interpretation. No metabolic stability information was applied to the model. 

Two significant principal components were extracted. The score plot of the two principal components is shown in Fig. 17.5, where the compounds are color-coded according to their metabolic stability (filled points represent unstable compounds,... 

Fig. 17.5. PCA score plot for the example on metabolic stability. Filled points represent compounds with metabolic stability <20% open points refer to compounds with metabolic stability >90%. (See text for explanation.)...

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