Inhibition potency

The neuropeptide Y (NPY) belongs to a family of peptides that includes peptide YY and pancreatic polypeptide, and it is associated with several diseases such as asthma, immune system disorders, inflammatory diseases, anxiety, depression and diabetes mellitus. NPY is found in the central and peripheral nervous system, and its biological functions are mediated by interactions with five receptor sub-types, i.e. Yl, Y2, Y4, Y5 and Y6. Several studies indicate that the feeding behavior is influenced by interactions between NPY and Yl and Y5. Deswal and Roy used Cerius descriptors and genetic function approximation QSAR to investigate the structural determinants for the inhibition potency of 24 compounds with the general structure 4 for the NPY Y5 receptor [31]. The best QSAR (H = 0.720,... 

FIGURE 4. Correlation between the relative inhibitory potencies of various drugs at high- and low-affinity [ H]MDA binding and between drug lipophilicities and inhibition potencies of [ H]MDA binding... 

HCV NS5B polymerase is an RNA-dependent RNA polymerase that is essential for viral replication. Thus, the inhibition of this enzyme offers a potential treatment for hepatitis C infection. Beaulieu et al. [51] report on the parallel optimization of enzyme inhibition potency and physical properties. In the first stage of hit characteri-... 

CDK2 is involved with controlling normal cell proliferation. Disregulation in cancer makes this a good antitumor target. Pevarello et al. [62] describe the parallel optimization of enzyme inhibition potency, cellular activity, physicochemical properties, and PK. A low MW hit (MW = 201) was specifically selected with the... 

Table 2 Inhibition Potency of Purine Riboside and its 8-aza Analogue...

Compounds 13-18 were tested for acetylcholinesterase inhibition activity and it was found that compounds 13 and 14 exhibited acetylchohnesterase inhibition activity with IC values (inhibition of enzyme activity by 50%) of 17 and 13 pM, respectively. Compounds 15-18 showed moderate enzyme inhibition activity with ICj, values of 35, 80, 76, and 100 pM, respectively. This bioactivity data suggested that the higher enzyme inhibition potency of compounds 13 and 14 may hypothesized due to the presence of a tetrahydrofuran ring incorporated in their stractures. Fnrthermore, compounds 1 and 2 exhibited nearly the same bioactivity and this indicated that C-7 hydroxyl group does not play any role in enzyme inhibition activity. 

A competitive inhibition screen is often the first step in understanding the DDI potential of a NCE. The definitive assessment of inhibition is the inhibition constant (K ), which provides not only the inhibition potency but also information on the mechanism of inhibition (competitive, non-competitive). However in the hit to lead profiling environment this approach is over-complex for the question being asked, and generates far too many samples to enable rapid screening of compound series. DDI assays based upon the IC50 principle are therefore favored. The relationship between K and IC50 for a competitive inhibitor is ... 

Table 8.2 Comparison of pharmacological target and CYP inhibition potencies for selected oral drugs, in order of DDI magnitude. Data compiled from [104-106],...

A number of conformationally restricted fluorinated inhibitors have been synthesized and evaluated. These smdies show that (1) subtle conformational differences of the substrates affect the inhibition (potency, reversible or irreversible character) (Figure 7.50), (2) a third inhibition process involving an aromatization mechanism could take place (Figure 7.51). When the Michael addition and enamine pathways lead to a covalently modified active site residue, the aromatization pathway produces a modified coenzyme able to produce a tight binding complex with the enzyme, responsible for the inhibition (Figure 7.51). ... 

To stabilize the tetrapeptide to aminopeptidase activity, amide bonds were reduced to the corresponding amines. A key observation was that modification of some of these peptide bonds negated the ability of a compound to serve as a substrate unlike before, this was independent of the identity of the a amino acids. While the peptide CllhS la was a good substrate for FTase, reduction of the first two amide bonds (cysteine, and aj-isoleucine) produced compound Id which was a potent inhibitor (IC50 20 nM) but was not a substrate (Table 2).33 Reduction of only one amide bond to give compounds lb and lc was also well tolerated in terms of inhibition potency, but both compounds were now substrates for FTase. This... 

FTIs requiring the presence of a thiol group for high inhibition potency have been described so far. There was also a significant effort to remove or replace the thiol... 

The system chosen to conduct CYP inhibition studies should be well characterized. This procedure requires initial time-course experiments and determination of linearity of metabolite formation with the chosen incubation time and enzyme concentration. After these experiments, the kinetic parameters (i.e., Km and Vmax) for each substrate used with six or more concentrations spanning from 1/3 to 3 A), and inhibition potencies (i.e., IC50 or K,) of typical inhibitors should be determined. This characterization does not need to be repeated for each batch or lot of test system. 

Yao C, Kunze KL, Trager WF, et al. Comparison of in vitro and in vivo inhibition potencies of fluvoxamine toward CYP2C19. Drug Metab Dispos 2003 31 565-571. 

FIGURE 4.8 Lead compound—Analog 5-1-9-3-4 with exceptionally high predicted inhibition potency against HIV PR. 

The influence of hydrophobic substituents on the inhibition potency of aryl a- and /3-D-gluco- and a-D-manno-pyranosides was also investigated. A linear correlation was demonstrated between the hyd-rophobicity of the substituent and the inhibiting power of the glycoside for o-, m-, and p-substituted-phenyl /3-D-gIucopyranosides.180,181,333,436... 

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