Inhibitors Selectivity

Dennis, M.S., Lazarus, R.A. Kunitz domain inhibitors of tissue factor-factor Vila. 1. Potent inhibitors selected from libraries by phage display. /. Biol. Chem. 269 22129-22136, 1994. 

The extent to which changes occur in different liquids depends on the type of liquid, type of refining, and whether it has been treated to provide further resistance to oxidation. The stability of liquids can be improved by the addition of oxidation inhibitors. Inhibitors selected to improve stability must be compatible with the other required properties of the liquid. 

Boilers and steam systems Steel steam lines can be inhibited by the use of a volatile amine-based inhibitor such as ammonia, morpholine or cyclohexylamine introduced with the feedwater. It passes through the boiler and into the steam system, where it neutralizes the acidic conditions in pipework. The inhibitor is chemically consumed and lost by physical means. Film-forming inhibitors such as heterocyclic amines and alkyl sulphonates must be present at levels sufficient to cover the entire steel surface, otherwise localized corrosion will occur on the bare steel. Inhibitor selection must take into account the presence of other materials in the system. Some amine products cause corrosion of copper. If copper is present and at risk of corrosion it can be inhibited by the addition of benzotriazole or tolutriazole at a level appropriate to the system (see also Section 53.3.2). 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

There is evidence that protease inhibitors selectively regulate the activity of specific digestive enzymes at the level of gene expression (Rosewicz et al., 1989). Specifically, soybean trypsin inhibitor increases secretion of proteases, including a form of trypsin that is resistant to inhibition but does not cause an increase in amylase secretion. Although the relationships between protease inhibitors and exocrine pancreatic secretion have received the most attention, pancreatic secretion is increased when potato fiber is added to the diet (Jacob et al., 2000), although the mechanism and signaling pathway have not been elucidated. 

Casanola-Martin GM et al. (2006) New tyrosinase inhibitors selected by atomic linear indices-based classification models. Bioorg Med Chem Lett 16(2) 324-330 Tan CY, Wainman D, Weaver DF (2003) N-, alpha-, and beta-substituted 3-amino-propionic acids design, syntheses and antiseizure activities. Bioorg Med Chem 11(1) 113-121... 

G. M. Graham, S. J. Dyer, K. S. Sorbie, W. R. SableroUe, P. Shone, and D. Frigo. Scale inhibitor selection for continuous and downhole squeeze application in HP/HT (high pressure/high temperature) conditions. In Proceedings Volume, pages 645-659. Aimu SPE Tech Conf (New Orleans, LA, 9/27-9/30), 1998. 

Tricyclic antidepressants Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors Antipsychotics Phenothiazines Risperidone Lithium... 

Note These data highlight the need for making comparisons of inhibitor selectivity on the basis of dissociation constants, rather than IC50 values. 

The development of Cat K inhibitors, with an emphasis on the fundamental biology, pharmacology and human clinical trials has been recently reviewed [1-3]. The medicinal chemistry of Cat K inhibitors has also been the subject of recent reviews [7,8]. This article reviews recent publications and meeting abstracts on the design of Cat K inhibitors, as well as developments in Cat K-related biology including animal models for the prediction of inhibitor efficacy, the potential for the separation of bone resorption and formation by Cat K inhibitors, inhibitor selectivity considerations and other potential indications for Cat K inhibitors. 

A series of non-ATP competitive, PH-domain-dependent allosteric inhibitors selective for AKT-1 and AKT-2 have previously been described [34]. Recently, new analogs, such as 22 and 23, were reported as potent and selective AKT-1 and AKT-2 inhibitors with improved aqueous solubility and cell permeability [35]. 

Wang Z., Canagarajah B.J., Boehm J.C., Kassisa S., Cobb M.H., Young P.R., Abdel-Meguid S., Adams J.L., Goldsmith E.J. Structural basis of inhibitor selectivity in MAP kinases. Structure 1998, 6, 1117-1128. 

The group at Millennium Pharmaceuticals has claimed MLN-8054 (97) to be the first kinase inhibitor selective for Aurora-A over Aurora-B, which gives robust inhibition of human tumor xenografts [228-230]. Treatment of cultured human tumor cells with 97 resulted in the accumulation of mitotic cells with spindle abnormalities, a phenotype consistent with selective Aurora-A inhibition. In a pharmacodynamic model the time-dependent accumulation of... 

A model for the structural relationship of /V-butyl-1 -deoxynojirimycin (131, Scheme 33) with ceramide, the substrate of ceramide glucosyltransferase, was suggested by Butters and coworkers. They conducted a comparative investigation on a range of 14 derivatives of 1-deoxynojirimycin substituted at the ring nitrogen and/or C-l, as well as 5 pyrrolidine-type inhibitors selected by superpositioning of the iminoalditol with a portion of the ceramide structure.364... 

H. C. Dorfmueller, V. S. Borodkin, M. Schimpl, X. Zheng, R. Kime, K. D. Read, and D. M. F. van Aalten, Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases, Chem. Biol., 17 (2010) 1250-1255. 

Iressa (ZD 1839) is an orally active tyrosine kinase inhibitor selective for the epidermal growth factor (EGF) receptor tyrosine kinase. Iressa is undergoing clinical trials in the treatment of various solid tumors, including head and neck cancer, breast cancer and non-small cell lung cancer. Its antitumor activity is derived from the fact that the EGF receptor and EGF signaling are... 

Over the years, many reversible competitive inhibitors selective for MAO A have been developed, including many a-methylamines. In contrast, very few effective MAO B-selective reversible inhibitors have been reported to date. Accumulated experience has indicated that a-alkylamines are inhibited steiically from binding to MAO B—and thus are MAO A selective. No complementary steric inhibition selective for MAO A is available [6b]. However, it was demonstrated that, while 5-fluoro-a-methyltryptamine (5) is a selective MAO A substrate, jS-substitution, as in p-chloro-/J-methylphenylamine (6), favors MAO B selectivity [28]. 

Interestingly, fluorination at the 2-position of 1-phenylcyclopropylamine (50), which is known as a selective inhibitor of MAO B relative to MAO A, reversed the selectivity and resulted in a potent inhibitor selective for MAO A [133,134] (Table 5). p-Substituted analogues of 1-phenylcycloropylamine (62b-e, 63b-e) are also MAO A-selective inhibitors and showed the same level of inhibitory potency as 62a and 63a. 

PEE-IV Inhibitors Selective inhibitors of phosphodiesterase IV (PDE4) are in development for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Two of them contain fluorine atoms roflumilast (preregistered) bears a difluoromethyl ether and AWD-12-281 (Phase II) has a single fluorine atom (Figure 8.51). 

Mechanism of Action An antiviral that acts as an HIV-1 protease inhibitor, selectively preventing the processing of viral precursors found in cells infected with HIV-1. Therapeutic Effect Prevents the formation of mature HIV cells. 

Creation of an optimum composition of modifiers (promoters, inhibitors, selective poisons, etc.) ... 

Monoamine oxidase (MAO) inhibitors, selective (Type A) moclobemide... 

Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). 

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS Selective Serotonin-Norepinephrine Reuptake Inhibitors... 

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