Serine proteases tryptase

In addition to the use in the synthesis of potential hepatitis C drugs, microwave-assisted chemistry has also been used in the synthesis of mast cell tryptase inhibitors, thrombin inhibitors, and Factor Xa inhibitors. The trypsin-like serine protease tryptase is the major secretory product of human mast cells and has been implicated as an inflammatory mediator in a number of conditions, especially asthma. Once released upon mast cell activation, the tryptase cleaves substrates that otherwise cause smooth muscle relaxation and thereby bronchi- and vasodilation. It is therefore not surprising that numerous reports on low molecular weight tryptase inhibitors have appeared. 

The serine protease tryptase is released from mast cells at sites of inflammation. Thus, tryptase inhibitors have potential for treating inflammatory disorders, such as asthma, allergic rhinitis, and inflammatory bowel disease. We explored a series of spirocyclic piperidine amide derivatives (1) as tryptase inhibitors and identified 2 (JNJ-27390467) as a potent, selective inhibitor of human p-tryptase (Ki = 3.7 nM). This compound has -700-fold selectivity vs. inhibition of trypsin, and greater selectivity vs. inhibition of 12 other serine proteases. In pharmacokinetics studies in dogs and rats, 2 showed... 

Many secreted proteins, as well as smaller peptide hormones, are acted upon in the endoplasmic reticulum by tryptases and other serine proteases. They often cut between pairs of basic residues such as KK, KR, or RR.214-216 A substilisin-like protease cleaves adjacent to methionine.217 Other classes of proteases (e.g., zinc-dependent carboxypeptidases) also participate in this processing. Serine carboxypeptidases are involved in processing human prohormones.218 Among the serine carboxypeptidases of known structure is one from wheat219 and carboxypeptidase Y, a vacuolar enzyme from yeast.220 Like the pancreatic metallocarboxypeptidases discussed in Section 4, these enzymes remove one amino acid at a time, a property that has made carboxypeptidases valuable reagents for determination of amino acid sequences. Carboxypeptidases may also be used for modification of proteins by removal of one or a few amino acids from the ends. 

Among the inhibition of other types of enzymes, several representatives of the class of (3-lactams have been found to effectively inhibit proteases. 2-Azetidinones tetrasubstituted have also been identified as powerful and selective inhibitors of thrombin, a serine protease involved in both venous and arterial thrombotic episodes. Analogous compounds have also been found to display inhibition towards tryptase. 

Because of their high selectivity against other serine proteases, for example thrombin, trypsin, or factor Xa, the development of bifunctional tryptase inhibitors has attracted much attention during recent years. Several classes of effective dibasic tryptase inhibitor have been reported, recently [13,14, 23], Herein, we describe syn-... 

We have created efficient syntheses of remarkably potent and selective bifunctional tryptase inhibitors, which are also competitive and reversible, containing pyran moieties and hetero and non-hetero aryl diynes as scaffolds. Several modifications at the core templates and the linker moieties are well tolerated without significant loss of inhibition activity. In contrast with previous results published recently [32], it was also apparent from the aryl diyne inhibitors that the distance between the two terminal amino groups can be considerably less than 30 bonds in highly potent target compounds (e.g. 9 and 29 with 26 bonds each). The in-vitro potencies of the compounds were between 1 im for 26 and 1.3 nM for 15 with high selectivity against other serine proteases (trypsin, thrombin, and factor Xa, respectively) in... 

Inhibitors Against Human Mast Cell Tryptase A Potential Approach to Attack Asthma Tab. 3.2.3. Selectivity data for inhibitor 9 compared with other serine proteases. 

Neutral and acidic serine proteases released from mast cells-tryptase MCX may damage type IV collagen and the intercellular matrix. Eosinophil chemotactic factors... 

During inflammation, degranulation of immune cells releases serine proteases that pass through and bind to the capillary wall. Increased levels of Bik suppress these immune cell proteases and protect the extracellular matrix in arterial walls and connective tissue [4]. Bik inhibits phagocytic destruction of cells. Bik has been shown to inhibit elastases, granzymes A and K [4, 57], Mast cell tryptases (J3- and a-tetrameric forms with a molecular weight of 134 kDa) are resistant to aprotinin [58]. Lymphocytes serine esterase TL2 is not inhibited by Bik [59]. 

N-Substituted 3-hydroxy-5-arylamino-isothiazole-4-carboxamidines are potent, orally available, in vitro MEKl allosteric inhibitors, <2006BML5561> while amino-heterocycle-substituted isothiazoles are inhibitors of the TrkA kinase in cell assays <2006BML3444>. Benzisothiazolone derivatives are inhibitors of different serine proteases, such as cell tryptase <1998JME4854> and HLE <2003EJM421>. 

Human / -tryptase is a serine protease which is stored in large amounts in mast cell secretory granules, and represents the major protein component released upon degranulation [71]. Mast cells play a key... 

A method for the design of inhibitors for such proteases was published in Proceedings of the National Academy of Sciences of the USA by another colleague from the Max-Planck-Institute. Professor Luis Moro-der, who is also Professor of Biochemistry and Biotechnology and the Technical University Munich, presents the principle of polyvalency by structure-based design of mono- and bivalent inhibitors for tryptase, proteasome and serine proteases, e.g., FXa. 

A typical recent example comes from some work on tryptase inhibitors, tryptase being a serine protease of interest for the treatment of asthma. Compound 44, shown in Figure 8.2, was found to be a 2.5 nM inhibitor of human tryptase, but a 365 nM inhibitor of the mouse enzyme, and a 400 nM inhibitor of monkey tryptase. Larger species specificity effects than this have been observed for some renin inhibitors, including zankiren (Figure 8.2) and the... 

Cydohexylidene-protected glyceraldehyde imines were used by Annunzi-ata et al. [54,55] for the synthesis of a 6-lactam precursor of thrombin and tryptase inhibitors [54], as well as for the inhibitor of serine protease [55]. 

Vanderslice PS, Ballinger SM, Tam EK, Goldstein SM, Craik CS, Caughey GH. Human mast ceU tryptase multiple cDNAs and genes reveal a multigene serine protease family. Proc Natl Acad Sci USA 1990 87 3811-3815. 

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