Inhibitory activity

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

Inhibitory activity INID codes Inifer method InipolEAP22 Initiators... 

Cell Division Inhibitors. The most common mode of action of soil-appHed herbicides is growth inhibition, primarily through dkect or indkect interference with cell division (163). Such growth inhibitory activity is the basis for most pre- or post-emergent herbicides intended to control germinating weed seeds. In germinating seeds, cell division occurs in the meristems of the root and the shoot. Meristematic cells go through a cycle... 

A stmcturally related series of phenyfiiydrazones resulted ia the selection of compound A-007 [2675-35-6] (DEKK-TEC)(37) for the treatment of hormone-dependent tumors. A-007 is an antiestrogen that, ia contrast to tamoxifen, demonstrated inhibitory activity both ia the presence and absence of estradiol ia ZR-75-1 estrogen-dependent human breast cancer cells, and afforded more protection than tamoxifen ia the 7,12-dimethylbenz[i7]anthracene... 

Diphenylamine inhibits the development of scald disease during prolonged cold storage of apples and pears (42—45). It prolongs the fresh appearance of cut snapdragons (46), controls weather fleck in tobacco, inhibits algae formation, and shows growth inhibitory activity in potatoes (47). 

The inhibitory activity of sorbates is attributed to the undissociated acid molecule. The activity, therefore, depends on the pH of the substrate. The upper limit for activity is approximately pH 6.5 in moist appHcations the degree of activity increases as the pH decreases. The upper pH limit can be increased in low water activity systems. The following indicates the effect of pH on the dissociation of sorbic acid, ie, percentage of undissociated sorbic acid at various pH levels (76,77). 

Table 2. P-Lactamase Inhibitory Activity for Clavulanic Acid and Analogues ...

The mode of action of PMEA may be quite similar to the mechanism by which (3)-HPMPA accomplishes its selective inhibitory activity against herpes vimses. Eor PMEA to reach its active triphosphate form, it needs only two phosphorylation steps. The triphosphate derivative of PMEA has a much stronger affinity for HIV-1 reverse transcriptase than for cellular DNA polymerases (175). Whether it is actually incorporated into DNA and terminates the growing DNA chain is currentiy under investigation. 

An important benefit of QSAR methods is that no enzyme stmcture is required. However, a series of stmcturaHy related inhibitors of known stmcture and known inhibitory activity is required. The limitations of the method involve the difficulties in describing something as compHcated as a stmcture-function relationship in a single mathematical expression. 

Horie and coworkers synthesized a series of flavones that showed promising inhibitory activity against archidonate 5-lipooxygenase. This enzyme is responsible for the initiation of bioactive leukotrienes that are chemical mediators of anaphylaxis and inflammation. Under standard K-R conditions o-hydroxyarylketone 66 and anhydride 67 in presence of the corresponding anhydride 68 delivered flavones 69 in yields of 42-65%. Subsequent hydrogenation of 69 afforded the flavone inhibitors 70. 

Thiadiazolo[3,4-/]quinoline monoamine oxidase inhibitory activities were examined in (91YZ499), but the values were too high to compare with other pentanthrene type of heterocycles. 

The tjipanazoles (18, 19a-d, 20a-b) a group of A-glycosides of indolo-[2,3-a]carbazole, have been isolated from the moderately antifungal extract of the blue-green alga Tolypothrix tjipanasensis. These alkaloids do not exhibit antitumor or protein kinase C (PKC) inhibitory activity, which is in contrast with the... 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Oxo-4//-pyrido[],2-n]pyrimidin-2-yl]oxymethylsaccharin derivatives 418 exhibited human leukocyta elastase inhibitory activities (94EUP626378, 95USP5378720). 2-Substituted 4//-pyrido[l, 2-n]pyrimidin-4-one (419) is a potent human leukocyta elastase inhibitors (A", 1.79/xM) (96USP5512576). The 4//-pyrido[l,2-n]pyrimidin-4-one moiety was included in leukotriene antagonist 2-ethynylthiazole derivatives (98JAP(K) 98/195063)... 

To date, 152 species of flowering plants belonging to 46 different families, as well as a few species of mushrooms, mosses, ferns, and lichens, have been screened. Extracts from 20 seed plants have shown enough inhibitory activity to warrant further study. Leaf extracts of members of three families, Liliaceae, Pinaceae, and Labiateae, show a high incidence of antiviral agents. Several members of the Capri-foliaceae, on the other hand, contain virus-stimulating agents. 

Active caspases 8, 9 and 10 can convert caspase-3, the most abundant effector caspase from its pro-form to its active cleaved form. Cleavage of a number of different substrates by caspase-3 and also by caspase-6 and -7 which are two other executioner caspases besides caspase-3 then results in the typical morphology which is characteristic of apoptosis. Yet, the activation of caspase-3 and also of caspase-9 can be counteracted by IAPs, so called inhibitor of apoptosis proteins. However, concomitantly with cytochrome C also other proteins are released from mitochondria, including Smac/DIABLO. Smac/DIABLO and potentially other factors can interact with IAPs and thereby neutralize their caspase-inhibitory activity. This releases the breaks on the cell death program and allows apoptosis to ensue. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

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