Protease inhibitors, protection from

Morishita, M., et al. 1992. Novel oral microspheres of insulin with protease inhibitor protecting from enzymatic degradation. Int J Pharm 78 1. 

Liang JS, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, Sturley SL. HIV protease inhibitors protect apolipoprotein B from degradation by the protea-some a potential mechanism for protease inhibitor-induced hyperlipidemia. Nature Med 2001 7 1327-31. 

An expeditious route to the cyclic sulfamide HIV-1 protease inhibitors of type 145 and 146 (tetrahydro-l,2,7-thiadiazepine 1,1-dioxide derivatives) from 141 and 142 hinges on palladium-catalysed amidation reactions. These reactions of 144 and 143 were microwave promoted and provided, after removal of the cyclic ketal protecting group, moderate to good yields of (145, 57%) and (146, 66%) for example with R = NHCOCH2-2-naphthyl <06T4671>. 

Encapsulation within an enteric coat (resistant to low pH values) protects the product during stomach transit. Microcapsules/spheres utilized have been made from various polymeric substances, including cellulose, polyvinyl alcohol, polymethylacrylates and polystyrene. Delivery systems based upon the use of liposomes and cyclodextrin-protective coats have also been developed. Included in some such systems also are protease inhibitors, such as aprotinin and ovomucoids. Permeation enhancers employed are usually detergent-based substances, which can enhance absorption through the gastrointestinal lining. 

A buccal drug delivery system is applied to a specific area on the buccal membrane. Moreover, the delivery system ean be designed to be unidirectional in drug release so that it can be protected from the loeal environment of the oral cavity. It also permits the inclusion of a permeation enhancer/protease inhibitor or pH modifier in the formulation to modulate the membrane or the tablet-mucosal environment at that particular application site. While the irritation is limited to the well-defined area, the systemic toxicity of these enhancers/inhibitors and modifiers can be reduced. The buccal mucosa is well suited for this type of modification as it is less prone to irreversible damage [9]. In the event of drug toxicity, delivery can be terminated promptly by removal of the dosage form. 

Cardiopulmonary bypass, with extracorporeal circulation during cardiac artery bypass graft or heart valve replacement surgery, causes transient hemostatic defects in blood cells and perioperative bleeding. The protease inhibitor aprotinin (Trasylol) inhibits kalhkrein (coagulation phase) and plasmin (hbrinolysis) and protects platelets from mechanical injury. The overall effect after infusion is a decrease in bleeding. 

Polymers that are protease inhibitors and polymer-inhibitor conjugates are now widely investigated for their ability to protect proteins and peptides from proteolytic degradation. These molecules are effective in the immediate area surrounding the delivery device, so the effects on proteins that have diffused far from the delivery device are limited. Due to the fact that bioadhesives were used as the conjugating polymer, the delivery device may adhere to the intestinal lining. If this does happen, the diffusional distance of the protein from the device to the intestinal wall will be quite short. One barrier that the protease inhibitors do not affect is the cellular barrier. Biomacromolecules must still find a method to enter the cells or be taken up by phagocytosis. 

Inhibitors of proteases have also been developed from polymers. These molecules are as simple as a polymer chain, or much more complex. The mechanisms for protease inhibition are variable depending upon the type of molecule used specific protease inhibitors are available for conjugation to a polymer while other polymeric inhibitors inhibit all divalent cation dependent proteases. The development of these inhibitory polymers and polymer conjugates greatly increase the possibility to protect proteins from degradation in the gastrointestinal tract. 

Peptidomimetics in which one amide bond is replaced by a phosphinic acid (R-P(0H)(=0)-R phosphinic peptides ) are of interest as potential protease inhibitors [17-19]. These compounds have been prepared either from orthogonally protected phosphorus-containing monomers [17,18,20], or by forming the phosphorus-containing fragments on solid phase, as sketched in Figure 11.4 [19,21], Phosphinic acids have been prepared on solid phase mainly by reaction of carbon electrophiles with monoalkylphosphinates. As carbon electrophiles, acrylates, aldehydes, reactive alkyl halides, or a, 3-unsaturated ketones can be used. 

Many biological cells contain degradative enzymes (proteases) that catalyze the hydrolysis of peptide linkages. In the intact cell, functional proteins are protected from these destructive enzymes because the enzymes are stored in cell organelles (lysosomes, etc.) and released only when needed. The proteases are freed upon cell disruption and immediately begin to catalyze the degradation of protein material. This detrimental action can be slowed by the addition of specific protease inhibitors such as phenylmethyl-sulfonyl fluoride or certain bioactive peptides. These inhibitors are to be used with extreme caution because they are potentially toxic. 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

The asymmetric catalytic aldol reaction of a silyl enol ether can be performed in a double and two-directional fashion to give the 1 2 adduct in the silyl enol ether form with >99% ee and 99% de in 77% isolated yield (Scheme 8C.25) [59]. The present catalytic asymmetric aldol reaction is characterized by a kinetic amplification phenomenon of the product chirality, going from the one-directional aldol intermediate to the two-directional product (Figure 8C.8). Further transformation of the pseudo C2 symmetric product, while still being protected as the silyl enol ether, leads to a potent analog of an HIV protease inhibitor. 

The BB protease inhibitors are heat and acid stable, thus they survive both cooking (3J) and digestion (183. BB complexes with proteases in the small intestine of rodents and is excreted primarily as protease-protease inhibitor complexes in the feces. The decreased efficiency of protein utilization from foods rich in protease inhibitors may indirectly lower an individual s effective protein intake (19). This may, in part, protect animals on protease inhibitor-rich diets as shown in a lower incidence of skin, breast and liver tumors (20,21 ). 

Scheme 10 Carbonylative microwave syntheses of C2-symmetric HIV-1 protease inhibitors from protected starting aryl halides...

Inieraciions of the serine proteases with active-si ic di reeled inhibiiois me blocked by acylation. Therefore, in contrast to the active enzyme, the acyl enzyme is protected from being inactivated in plasma by rapidly acting inhibitors (protection against inactivation). 

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