IC50-value

Surmountable antagonism can be quantified by pA2 values. Insurmountable antagonism through IC50 values that in some cases can be corrected for the strength of stimulation in the system. 

The IC50 value is that concentration of a drag that reduces the activity (or binding) of another drag to an enzyme by 50%. Under certain conditions it can used to express the affinity of the enzyme inhibitor. 

Na+/Ca2+ Exchangers. Figure 6 Chemical structures of some NCX inhibitors. IC50 values for NCX inhibition of drugs belonging to different chemical families. 

The IC50 values for the inhibition of [3H]-nitrendipine binding for the metabolite has a value of 203 nM in comparison to SR 33557 which reaches a value of only 0.6 nM. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

Table 2.2 IC50 values of selected gold(lll) complexes against the human ovarian carcinoma A2780 cell lines sensitive (S) or resistant (R) to cisplatin. Adapted from Ref [47],...

Table 6.3 Ki or IC50 values for biologically important enzymes and gold complexes. Adapted from Shaw [17].

IC50 values of cisplatin and AU55 and Figures 29a and b show the course of cell viabilities in dependence of the molar concentrations in case of melanoma cells. 

ICso is defined as the concentration of drug required to inhibit cell growth by 50% compared to a control. The IC50 values were calculated from the graphs obtained from the in vitro cytotoxicity assays and are the average of three independent experiments, each performed in triplicate. 

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

Bristol-Myers Squibb has recently disclosed two different series of carbamate-based FAAH inhibitors. The first of these is a series of 4,5-diaryl-imidazoles in which 30 compounds are specifically claimed, an example being compound (57). This compound is reported to have an IC50 value of < 10 nM. In addition, (57) was also active in vivo in rodent models of chemo-induced, thermal and neuropathic pain [72]. The second series of compounds is based on oxime carbamoyl FAAH inhibitors such as (58). Compound (58) is reported to have an IC50 value of < 10 nM and activity in rodent models of inflammatory pain, thermal pain and inflammatory oedema [73]. 

A series of dioxane carbamate inhibitors has recently been disclosed by Sanofi-Aventis. No biological data are provided for specific compounds, although most compounds are described as having IC50 values for FAAH inhibition ranging from 0.005-1 Compound (59) is one of over 25 compounds specifically claimed [74]. 

Sanofi-Aventis has disclosed a series of piperidine- and piperazine-alkyl carbamates as cannabinoid and/or FAAH modulators. No compounds are specifically claimed in the patent. Compound (60) is reported to have an IC50 value of 85 and is active in a mouse pain model [75]. 

Another arachidonyl-based inhibitor of FAAH is arachidonyl serotonin (62), which was reported to inhibit FAAH from rat basophilic leukaemia cells with an IC50 value of 5.6 pM, and with very little affinity at CBi receptors [76]. 

Finally, derivatives of the endogenous compound 2-octyl- y-bromoacetate (65) have been reported as FAAH inhibitors [79]. In a limited SAR study, it was found that replacement of the bromine with a chlorine atom had little effect on affinity. The replacement of the alkyl chain with oleyl-chain mimics resulted in an increase of affinity for FAAH (approximately 5-fold). The removal of the halogen and replacement with either a proton or methyl resulted in inactive compounds. The most potent compound identified in this series was compound (66) with an IC50 value of 0.6/rM [79]. 

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