Acrylate enzyme inhibitor

A novel concept of using bioadhesive polymers as enzyme inhibitors has been developed [97]. Included are derivatives of poly acrylic acid, polycarbophil, and car-bomer to protect therapeutically important proteins and peptides from proteolytic activity of enzymes, endopeptidases (trypsin and a-chymotrypsin), exopeptidases (carboxypeptidases A and B), and microsomal and cytosolic leucine aminopeptidase. However, cysteine protease (pyroglutamyl aminopeptidase) is not inhibited by polycarbophil and carbomer [97]. 

The bacteriostatic activity of a series of substituted trans-3-benzoylacrylic acids has been successfully correlated by Hansch linear free energy relations involving polar and partition substituent constants. The activity-lipophilicity relations for this series closely parallel those found previously for other antibacterial agents, with an ideal lipophilic character for gram-positive cells of 6.1 and, for linear dependence, a slope of 0.7. A polar reaction constant, p, of about —0.6 to —0.7 is given. A possible mode of action for these acids and their related substituted cis- and trans-3-benzoyl acrylic acids and esters is discussed as an enzyme-inhibitor interaction. 

Access to peptide mimetics and enzyme inhibitors was accomplished by the construction of pyridylalanine derivatives [139], Once incorporated into peptides, the resultant structure was capable of coordinating to cations. The desired amino acid 397 was prepared from 396 by a Heck reaction using an acrylic acid ester followed by hydrogenolysis. This species could then be incorporated into the desired mimetic system 398 that was capable of complexation with europium ions. 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

The failure in increasing residence time of mucoadhesive systems in the human intestinal tract has led scientists to the evaluation of multifunctional mucoadhesive polymers. Research in the area of mucoadhesive drug delivery systems has shed light on other properties of some of the mucoadhesive polymers. One important class of mucoadhesive polymers, poly(acrylic acid) derivatives, has been identified as potent inhibitors of proteolytic enzymes [72-74]. The interaction between various types of mucoadhesive polymers and epithelial cells has a direct influence on the permeability of mucosal epithelia by means of changing the gating properties of the tight jrmctions. More than being only adhesives, some mucoadhesive polymers can therefore be considered as a novel class of multifunctional macromolecules with a number of desirable properties for their use as delivery adjuvants [72,75]. 

Clavulanic acid is also a mechanism-based inhibitor and its mode of action is believed to involve ring opening of the initially formed acyl-enzyme complex (18) to the keto-derivative (19), which may then tautomerise to the hydrolytically more stable -amino-acrylate (20) Scheme 6.4). This transiently inhibited form may hydrolyse to re-release active enzyme or react further with the enzyme to produce irreversibly inhibited forms. It has been shown that approximately 115 molecules of clavulanic acid are destroyed per molecule of enzyme before the j8-lactamase is irreversibly inactivated. Whilst irreversibly inactivated forms are known to exist, the nature of these products is not yet known. Possible structures are (21) and... 

Lipopurealin-A (141), lipopurealin-B (142), and lipopurealin-C (143) exhibited inhibitory activities on Na,K-ATPase from porcine brain and dog kidney, lipopurealin-B being the most potent inhibitor. In cardiac Na,K-ATPase all three alkaloids showed only weak activity. In addition, myosin K,EDTA-ATPase was markedly activated by purealin, whereas the enzyme was inhibited by lipopurealin-B (202). Purealidin A (146) showed weak inhibitory activity (22% inhibition at 10 M) on Na,K-ATPase, and had no effect on myosin K,EDTA-ATPase. These results suggest that the acryl part of purealin (122), lacking in purealidin A (146), is important for the activity of these ATPase inhibitors (J04). lanthesines B (106), C (93), and D (107) exhibited inhibitory activity against dog kidney Na,K-ATPase with IC50 values of 440, 50, and 280 pM,... 

These normally contain anionic and nonionic surfactants, builders (such as sodium tripolyphosphate, acrylate polymers or copolymers, or sodium carbonate), ion exchangers (such as polyacrylic acid or zeolite), corrosion inhibitor (sodium silicate), processing aids, antiredeposition agent (such as sodium carboxymethylcellulose), whitener or optical brightener (stilbene derivative), dye, and perfume. They may also contain bleach (sodium perborate or percarbonate), enzymes (a protease and/or an amylase), foam suppressor, filler/processing aid (sodium sulfate), fabric softener (quaternary ammonium salt immobilized on a clay), and solubilizer. The surfactant concentration of a heavy duty powder is in... 

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