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Document Figure 1 Diagram of the human kinin-kallikrein system including the native ligands for B1 and B2 receptor subtypes. feedback loop. The cleavage of bradykinin from HMWK is highly localized since pre-kallikrein and substrate (HMWK) circulate as a complex. Page 120 Another kinin, Lys-bradykinin (also known as kallidin), is produced via the action of the tissuekallikrein enzyme on LMWK. This enzyme is found in many tissues, either in the form of a precursor requiring activation or as an active enzyme. In contrast to plasma kallikrein, which preferentially acts upon HMWK, tissue kallikrein can release kallidin from either HMWK or LMWK. Through the action of aminopeptidases, kallidin can subsequently be converted directly into bradykinin. This enzyme is present in both the plasma and on the surface of epithelial cells. Both bradykinin and kallidin can be degraded by a variety of plasma and cell surface enzymes (kininases) [7]. The most widely recognized of these enzymes are kininase I, kininase II (angiotensin converting enzyme, ACE), and carboxypeptidase N. In plasma, kininase I cleaves the C-terminal arginine from both bradykinin and kallidin to form [des-Arg 9] kinins. These [des-Arg 9] kinins are known to act as agonists of B1 receptors that are present in some species and have been implicated in the pathophysiology associated with prolonged inflammation [8–10]. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_120.html (1 of 2) [4/5/2004 4:56:27 PM]
Document Page 121 Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer's disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. In contrast to the adverse physiologies associated with bradykinin release, there is a growing body of literature that implicates bradykinin as a protective agent during periods of cardiac or renal stress [14–16]. In this regard there is substantial evidence that the cardioprotective effects afforded by ACEinhibitor treatment are a result of metabolically preserving bradykinin and are therefore mediated by bradykinin B2 (and possibly B1) receptors [17–18]. These results point to a possible therapeutic role for a kinin receptor agonist. Overall, the kinins are an important part of a well-organized physiological system. The various aspects and interdependencies of the kinin system have been, and continue to be, the focus of intensive research efforts in many laboratories. Many pharmaceutical companies have identified this system as an ideal site for therapeutic intervention in many inflammatory diseases. Hence, there have been many diverse approaches taken toward the discovery of antagonists (peptide and nonpeptide) of B2 and B1 receptors. This review focuses on the structure-based design strategies pursued in our laboratories during the past several years. II. Ligand-Based Investigations A. The Solution Conformation of Bradykinin In the late 1980s when we began the pursuit of bradykinin receptor antagonists, information of relevance to medicinal chemists was scarce. For example, not one nonpeptide antagonist of this receptor was known, nor were any series upon which to base a structure-activity relationship. Moreover, all publications described bradykinin as being highly flexible in an aqueous environment, such that no structural mimetics could be rationalized. Of course the receptors had not been cloned at that time so nothing was known about the primary sequence of the receptor or the three-dimensional structure. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_121.html [4/5/2004 4:56:29 PM]
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Page 139 and 140: Document cubation of phosphotyrosin
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document Figure 5 Some compounds wh
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document Phosphoglycerate kinase (P
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