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Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligand-chelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed.

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Several lines of evidence support protective as well as deleterious effects of oleic acid (OA) on Alzheimer's disease (AD) and other neurological disorders; however, the bases of these effects are unclear. Our investigation demonstrates that amyloid precursor protein (APP) 695 transfected Cos-7 cells supplemented with OA have reduced secreted amyloid-beta (Aβ) levels. An early-onset AD transgenic mouse model expressing the double-mutant form of human APP, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings when they were fed a high-protein, low-fat (18% reduction), cholesterol-free diet enriched with OA. These mice exhibited an increase in Aβ40/Aβ42 ratio, reduced levels of beta-site APP cleaving enzyme (BACE) and reduced presenilin levels along with reduced amyloid plaques in the brain. The decrease in BACE levels was accompanied by increased levels of a non-amyloidogenic soluble form of APP (sAPPα). Furthermore, the low-fat/+OA diet resulted in an augmentation of insulin-degrading enzyme and insulin-like growth factor-II. These results suggest that OA supplementation and cholesterol intake restriction in a mouse model of AD reduce AD-type neuropathology.

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