Ki-value

The Ki value is the dissociation constant of an enzyme-inhibitor complex. If [E] and [I] are the concentrations of enzyme and its inhibitor and [El] is the concentration of the enzyme-inhibitor complex, there is an equilibrium of complex formation and detachment as follows ... 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

In 2004, Alterman et al. apphed their cyanation protocol to the synthesis of N-(t-butyl)-3-(4-cyanobenzyl)-5-isobutylthiophene-2-sulfonamide [61]. Deprotection of the sulfonamide followed by carbamate formation via reaction with butyl chloroformate finally gave the target compoimd for biological evaluation as a selective angiotensin 11 AT2 receptor agonist (Scheme 65). The cyano derivative, however, showed only a low affinity for the AT2 receptor (Ki value >10 p,M). 

Can we rationalize these observations in terms of ligand-field or other effects The data that we have presented in Fig. 8-14 refers to the log Ki values for each ligand with the high spin divalent metal ions. The sequence reflects a number of simple properties of the cations. Firstly, the trend closely parallels the ionic radii... 

However, consideration in terms of the ionic radius or the LFSE shows that both factors predict that the maximum stabilities will be associated with nickel(ii) complexes, as opposed to the observed maxima at copper(ii). Can we give a satisfactory explanation for this The data presented above involve Ki values and if we consider the case of 1,2-diaminoethane, these refer to the process in Eq. (8.13). 

What happens if we look at the K2 or Ki, values for didentate ligands In general, the Kj values show stability patterns which closely parallel those for K. However, the values are different. Figure 8-17 presents K, data for transition-metal complexes of 1,10-phenanthroline and 1,2-diaminoethane (Eq. 8.14). 

Table 9-3. log Ki values for iron(iii) and lead(ii) halide complexes. 

The above-mentioned set of Ki values are deduced from analyses based on the hyperfine constants of mononuclear FeS4 centers. However, we have already stressed that local parameter values are not necessarily transferable from one type of iron—sulfur center to an-... 

Plasmepsin II. The malarial aspartyl protease plasmepsin II has a significant homology (35%) to cathepsin D. Correspondingly, the very same approach as for the cathepsin D inhibitors (see above) was followed. The best inhibitors have Ki values of 2-10nM, a molecular weight <650, moderate selectivity vs. cathepsin D, the most closely related human protease, log P values <4.6, and no apparent binding to human serum albumin, for example, compound 36 Ki plasmepsin II = 2.0nM, Ki cathepsin D = 9.8nM Fig. 16.5) [111]. 

First, the order of ky values in different solvents is quite reasonably interpreted as a nucleophilicity order - e.g. ( 113)280 > HjO CH3NO2 > C2H5OH) and second, the k rate is (as is the k2) greatly reduced by steric crowding . Of course, a nucleophilic attack by solvent is a very likely process, a priori. In any solvent, the solvent itself will be the poorest nucleophile that can be studied since poorer ones will not effectively compete. Thus the k term of equation (21) corresponds to the ki value. The aquo intermediate of scheme (22) has been trapped by using reactions in the presence of OH , a poor nucleophile but good base . ... 

This type of in vitro study is relevant because it mimics likely physiological conditions. Red cells contain 1-2 mM GSH so the formation of glutathione complexes would be a likely consequence when auranofin metabolites enter red cells [112, 113]. Compared with typical in vivo gold concentrations of 10-15 pM observed in patients, the Ki values for the four gold complexes are less than anticipated. This indicates that chrysotherapy can greatly depress GSH-Pxase activity in vivo so the normal cellular redox balance would be displaced, favoring the accumulation of H2O2 and possibly GSH [3, 79, 114]. 

Ki values and Hill coefficents determined by competition experiments for 1.0 nM [ H]LSD(+[10- M]Ketanserin)-labeled sites in rat frontal cortical homogenates. Data from Shannon et al. 1984. 

Using these equations, the KI values for four known pheromone components are estimated to be 1807.7 for Me2,Me5-17 H, 1790.6 for Me5,Me9-17 H, 1788.6 for Me5,Mell-17 H, and 1783.5 for Me7, Mell-17 H. These positional isomers separately elute from a capillary GC column in a coincidental order with these KI values [105,106],indicating the usefulness of IEX(opt) for the pheromone research. 

Gibbs, M. A., Thummel, K. E., Shen, D. D., Kunze, K. L., Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes comparison of Ki values and impact of CYP3A5 expression, Drug Metab. Dispos. 1999, 27, 180-187. 

For this reason, the in vivo effects of an M BI cannot be predicted solely on the basis of its affinity K (dissociation constant ofthe enzyme-substrate complex) for the CYP, and they are usually more pronounced for a given Ki value than that observed with a reversible inhibitor [12]. 

In order to optimize the size and shape of the catalyst particle, activities for pellets produced from the same material were measured for different sizes and shapes. Some of the results are reported in Table 2. The measured ki values show that 9-mm particles are 35% more active than 12-mm particles and that the activity of a 9-mm VK69 is 2.3 times better than a conventional VK38 in the form of a 12-mm Daisy. 

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