Inhibitors worked examples

Thompson et ah, 1998 Marquis et al., 1999). Once each half was optimized, more SBDD cycles were needed to tweak the full molecule. This work resulted in numerous potent and selective cathepsin K inhibitors an example is shown in Fig. 17.3. Improvements in potency and selectivity of the compounds shown in Fig. 17.3 are listed in Table 17.2. Much of this work was recently summarized in Veber and Cummings (2004). 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

One more example of a thiazole ring enclosing dmg is known in the unique xanthine oxidase inhibitor febuxostat 29 (Uloiic) which was accepted by the FDA in 2009 [85]. This inhibitor works by hindering xanthine oxidase in a non-competitive manner. Subsequently, the quantity of the oxidation product mic add is decreased. Thus, it is an extremely well-organized action for h3rpemricemia in gput. 

Amides can also be very effective inhibitors. For example, dicyandlamide provides steel with >90% protection in 4% (1N) HCI (also in H2SO4) up to at least 129°F (54°C). Nitriles, such as cinnamonitrile, are good inhibitors for both iron dissolution and hydrogen absorption, but they are not widely used. In contrast, imidazolines are popular. Kataoka and Takada filed patents on various imidazoline derivatives, and Patel et al. found that benzimidazoles are effective for copper and brass in HCI. A combination of amino and azo groups seems to work very well. For example, D Errico discovered that dialkylaminomethyi aromatic triazoles are effective in 5% HCI at 171°F (77°C). 

The Kiev period was very fruitful for Antropov. He further elaborated his ideas on corrosion inhibitors. For example, he proposed a new quantitative theory, which could explain and permit to calculate the intermoleculary and intramoleculary synergetic effects of the inhibitors action and gave rise to the purposeful choice or synthesis of the inhibitors. This was called by him as the formal theory . It is widely used now by most scientists, which are working in the field of inhibiting metal protection. 

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. 

Metal- Working and Hydraulic Fluids. In the preparation of fluids for metal-working and hydrauflcs, the trend has been to replace organic-based materials with aqueous-based materials. Neodecanoic acid has found apphcation in these newer fluids as a corrosion inhibitor and a viscosity improver. For example, neodecanoic acid is used in an aqueous hydrauflc fluid concentrate for corrosion inhibition and improved antiwear properties (101), in the preparation of a thickened aqueous hydrauflc fluid to reduce viscosity loss (102), and in a water-soluble metal working oil to reduce corrosion (103). In a similar vein, neodecanoic acid has been used in antifreeze concentrates for corrosion inhibition (104). 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

A recent example of the success of the bisubstrate, transition state design approach comes from the work of Pope and coworkers (Pope et al., 1998a-c Brown et al., 2000) on the design of inhibitors of bacterial isoleucyl tRNA synthetase... 

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