Weak inhibitors

Azide, thiocyanate, and cyanate also have been shown to bind to Cluster C (152). Although they are weak inhibitors of the enzyme, they cause marked changes in the EPR spectrum of Cluster C (153), converting the Credi state (with all g-values below 2) to a state in which all g-values are above 2. 

Cross-reactions with aspirin and NSAIDs are of practical importance. Typically, AIA patients are sensitive to all NSAIDs that preferentially inhibit COX-1 (table 2). Acetaminophen (paracetamol), a weak inhibitor of COX-1, is regarded as a relatively safe therapeutic alternative for almost all patients with AIA. High doses of the drug (>1,000 mg) have been reported to provoke mild, easily reversed bronchos-pasm in some AIA patients [13]. Some rare, well-documented cases of coexistence of aspirin and paracetamol sensitivity have been described. However, according to a recent meta-analysis, less that 2% of asthmatics are sensitive to both aspirin and paracetamol [14]. 

These types of antidepressant were introduced around 10 years after the SSRIs. They include the serotonin noradrenaline reuptake inhibitor venlafaxine and the selective noradrenaline reuptake inhibitor reboxetine. Although there are fewer data about these drugs, clinical experience has shown they are well tolerated and, unlike the SSRIs, they are only weak inhibitors of drug metabolism (Kent, 2000). Depression is a common psychiatric disorder seen in the elderly and often remains untreated or inadequately treated (Forsell and Fastbom, 2000). Venlafaxine was shown to improve the mood in a group of 36 older patients without any effect on cognitive function, an important consideration where there is the possibility of the coexistence of mild or undiagnosed dementia (Tsolaki et al., 2000). 

During the chain oxidation of hydrocarbons, sulfides and disulfides terminate chains by reacting with peroxyl radicals [40,42,44], which, as opposed to phenols, are weak inhibitors (see Table 17.6). The mechanism and stoichiometry of the termination reaction by sulfides remain yet unclear. Since sulfenic acid is an efficient scavenger of free radicals, the oxidation of tetralin in the presence of dialkylsulfoxide occurs only if the initiation rate v > vimin is proportional to the concentration of sulfoxide [5], so that the rate of oxidation is... 

Acceptors of alkyl radicals are known to be very weak inhibitors of liquid-phase hydrocarbon oxidation because they compete with dioxygen, which reacts very rapidly with alkyl radicals. The situation dramatically changes in polymers where an alkyl radical acceptor effectively terminates the chains [3,49], The study of the inhibiting action of p-benzoquinone [50], nitroxyl radicals [51-53], and nitro compounds [54] in oxidizing PP showed that these alkyl radical acceptors effectively retard the oxidation of the solid polymer at concentrations ( 10-3 mol L 1) at which they have no retarding effect on liquid hydrocarbon oxidation. It was proved from experiments on initiated PP oxidation at different p02 that these inhibitors terminate chains by the reaction with alkyl macroradicals. The general scheme of such inhibitors action on chain oxidation includes the following steps ... 

The serotonin-norepinephrine reuptake inhibitors include venlafaxine and duloxetine. Venlafaxine is an inhibitor of 5-HT and NE reuptake and a weak inhibitor of DA reuptake. Desvenlafaxine (Pristiq) was recently approved by the FDA. The dose is 50 mg once daily. 

Tricyclic antidepressants such as imipramine (25), clomipramine (26), amitriptyline (27), and doxepine (28) were found to be weak inhibitors of GST Pl-1 in vitro. Inhibition of GST Pl-1 was enhanced with the introduction of a chloro group on the dibenzazepine ring (25 40% inhibition at 15 mM 26 70% inhibition at 10 mM). The same result was observed with the substitution of an oxygen for a carbon in the heptadiene ring (27 18% inhibition at 10 mM 28 48% inhibition at 15 mM) [35],... 

Several observations regarding this aspect have been published, and are briefly mentioned here. 5,6-Dideoxy-6-C-phosphono-D-arabino-hexofuranose (135), an isosteric phosphonate analog of D-arabinose 5-phosphate, is apparently converted, in the presence of enolpyruvate phosphate, into 3,8,9-trideoxy-9-C-phosphono-D-mcmno-2-nonulosonic acid (136) under catalysis by KDO 8-phosphate synthetase from Escherichia coli K 235. Compound 136, an isosteric phosphonate analog of KDO 8-phosphate, is a product inhibitor of the synthetase, and, by the nature of the phosphonate group, is not subject to dephosphorylation as catalyzed by KDO 8-phosphate phosphatase156 (see Scheme 40). Compound 119 (see Scheme 33) is a weak inhibitor of KDO 8-phosphate synthetase.81 KDO inhibits KDO 8-phosphate phosphatase,139 and D-ribose 5-phosphate has an inhibitory... 

A systematic study has confirmed the low activity of EHs toward cycloalkene oxides (1,2-epoxycycloalkanes, 10.123) [184], In the presence of mouse liver microsomal EH, activity was very low for cyclopentene oxide and cyclohexene oxide (10.123, n = 1 and 2, respectively), highest for cyclo-heptene oxide (10.123, n = 3), and decreased sharply for cyclooctene oxide (10.123, n = 4) and higher homologues. Mouse liver cytosolic EH showed a different structure-activity relationship in that the highest activity involved cyclodecene oxide (10.123, n = 6). With the exception of cyclohexene oxide, which exhibited an IC50 value toward microsomal EH in the p.M range, cycloalkene oxides were also very weak inhibitors of both microsomal and cytosolic EH. 

Chemistry. Nicotinamide (NAm), a product of PARP-1 enzymatic action on NAD and a weak inhibitor of PARP-1 activity (Curtin, 2006), was used as a model for the first PARP-1 inhibitors, including benzamide and 3-aminobenzamide (3AB) (Shall, 1975) (Fig. 7a). Benzamide and 3AB inhibit PARP-1 activity in the mM range and may also inhibit other PARP family members e.g., PARP-2 and tankyrase Smith et al, 1998 Ame et al, 1999), thus lacking the potency and specificity required for therapeutic purposes. Banasik et al developed 1,5-dihydroisoquinoline (Fig. 7c) and a variety of other inhibitors (Banasik et al, 1992), which were used in turn to develop even more inhibitors with greater specificity. 

GatCAB amidotransferase.This natural product mimics the charged 3 -terminus of aa-tRNA and has been used as a tool for the study of protein biosynthesis. The parent compound 22 is a very weak inhibitor of AdT. The amino acid chain is related to tyrosine and differs from the glutamic and aspartic side chains transformed in the kinase or the transamidase steps. Replacement of the methoxyphenyl moiety of puromycin by carboxylic acid derivatives (23-26) improved the ability to inhibit this AdT. Stable analogues of the transition state in the last step of the transamidation process (27-29) where the carbonyl to be attacked by NH3 is replaced by tetrahedral sulfur or phosphorus atom with a methyl group mimicking ammonia exhibited the highest activity. 

Furthermore, Meldal et al. developed the idea to combine the substrate cleavage on the solid phase with an inhibitor library assay in which a substrate is synthesized and coupled to a library of putative inhibitors (34) (Fig. 10.4). The incubation of such an inhibitor library with enzymes led to cleavage and hence fluorescence in beads containing weak inhibitors. Beads containing strong inhibitors re-... 

A term used to describe inhibition induced by a second inhibitor. A particular inhibitor (F) may be a weak inhibitor for a certain enzyme however, in the presence of a second inhibitor (F), inhibition is greatly enhanced. An example of such a system is the inhibitory effect of inorganic pyrophosphate on trichodiene synthase by certain aza analogues Both enantiomers of serine are weak inhibitors of y-glutamyl transpeptidase (L-serine has a Ki value of 10.7 mM), but in the presence of borate ion, they are potent inhibitors ... 

Pharmacology Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 

In the experiments reported above, no strong indications were obtained that the allelochemlcals interfered directly with the synthesis of ATP by acting on the energy transfer pathway complex). However, some of the compounds did inhibit ATP hydrolysis, as measured with preparations in which the mitochondria had been ruptured by freeze-thawing (Table III). The flavones (except fl one itself) and cinnamic acids strongly inhibited the Mg -ATPase, whereas the benzoic acids and coumarlns were weak inhibitors, i.e., less than 15% inhibition at 10 mM concentrations. Results obtained with quercetin (Table III) agree with published reports in which the compound was shown not to affect ATP synthesis but to inhibit the hydrolysis of ATP by the mitochondrial Mg -ATPase (30). 

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