Therapeutic inhibitors

The role of therapeutic inhibitors of elastase is to prevent the degradation of extracellular matrix proteins following the release of elastase from activated neutrophils. Tb determine which inhibitors of elastase may be of therapeutic value, there are several properties that must be considoed. These include rate of wmnMjnaaw tmrjivsti , selectivity, ize, tn vnHKi i y to rnBCtiv inn ... 

Contents I. Introduction II. Marine algae as Therapeutic Inhibitors 268... 

II. MARINE ALGAE AS THERAPEUTIC INHIBITORS AGAINST ALLERGIC DISORDERS... 

The first illustration of the potential of 35-kDa protein as a therapeutic inhibitor of inflammatory disease in vivo was produced using a guinea pig skin inflammation model. Purified recombinant vCKBP completely inhibited local eosinophil infiltration induced by eotaxin, a feature of allergic inflammatory reactions [16]. Similarly, the related vCKBP from orf vims has been recently shown to inhibit migration of monocytes in a mouse acute skin inflammation model induced by LPS [23]. 

Finally, a variety of chemicals, including PAHs, chlorinated biphenyls, and flavonoids were demonstrated to interact with (spectral binding) and to inhibit P450 2A6 (as well as P450 2A13) [477]. This inhibition has relevance to potential use of some of these compounds as therapeutic inhibitors as well as to interactions in the activation of them by P450 2A6 (and 2A13) [351],... 

An impressive example of the application of structure-based methods was the design of a inhibitor of the HIV protease by a group of scientists at DuPont Merck [Lam et al. 1994 This enzyme is crucial to the replication of the HIV virus, and inhibitors have bee shown to have therapeutic value as components of anti-AIDS treatment regimes. The star1 ing point for their work was a series of X-ray crystal structures of the enzyme with number of inhibitors boimd. Their objective was to discover potent, novel leads whid were orally available. Many of the previously reported inhibitors of this enzyme possessei substantial peptide character, and so were biologically unstable, poorly absorbed am rapidly metabolised. 

Three classes of oral therapeutic agent are available for treating patients with diabetes mellitiis (NIDDM) the arylsulfonylureas (known simply as sulfonylureas), biguanides, and a-glycosidase inhibitors. Since 1977, only the sulfonylureas have been approved for use in the United States, although the other classes are used elsewhere. 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

Therapeutic opportunities for NO synthons include angina, for which nitroglycerin is effectively used, as well as penile erectile dysfunction. NOS inhibitors have demonstrated some protection in cerebral ischemia models and may be potentially beneficial in alleviating cell death associated with cerebral ischemia. l-NMA is under clinical study for treatment of sepsis. 

The phosphorodithioates DNA derivatives have been shown to bind specifically to complementary DNA or ENA sequences to form stable adducts. Because they are also highly resistant to degradation by cellular exonucleases, these derivatives can be useful both for appHcations in research and as therapeutic dmgs. Phosphorodithioate DNA has been shown to stimulate Rnase H activity in nuclear cell extracts and is a potent inhibitor of HIV type-1 reverse transcriptase (56). 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

Normally, dietary tyramine is broken down in the gastrointestinal tract by MAO and is not absorbed. In the presence of MAOI, however, all of its potent sympathomimetic actions are seen. Other side effects of MAOI include excessive CNS stimulation, orthostatic hypotension, weight gain, and in rare cases hepatotoxicity. Because the monoamine oxidase inhibitors exhibit greater toxicity, yet no greater therapeutic response than other, newer agents, clinical use has been markedly curtailed. The primary use for MAOIs is in the treatment of atypical depressions, eg, those associated with increased appetite, phobic anxiety, hypersomnolence, and fatigues, but not melancholia (2). 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

Pseudopterosin A is a member of a group of marine natural products which show potent antiinflammatory properties, but which are not prostaglandin biosynthesis inhibitors. Structurally similar to phosphatidyl inositol, they may function as phospholipase inhibitors, and, as such, may be the forerunners of a new class of therapeutic agents. 

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