Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1996-08-08
1999-03-23
Marschel, Ardin H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
435 6, 436501, 530300, 530350, 536 221, 536 231, 536 241, 536 243, 536 2431, 536 2432, 536 2433, 544 1, 544232, 544233, 544235, 544236, 544238, 544239, C07D23700
Patent
active
058861777
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is directed to alkylene glycol monomeric units and to oligomers constructed from these units. The oligomers can be synthesized to have either random or predefined sequences of monomeric units and can be joined via phosphate linkages, including phosphorothioate, phosphodiester, and phosphoramidate linkages. Each of the monomeric units can include a chemical moiety thereon for binding of the oligomeric structures to proteins, nucleic acid, and other biological targets. In preferred embodiments, the compounds of the invention act as inhibitors of enzymes such as phospholipase A.sub.2 and are used for the treatment of inflammatory diseases including atopic dermatitis and inflammatory bowel disease.
BACKGROUND OF THE INVENTION
Phospholipases A.sub.2 (PLA.sub.2) are a family of enzymes that hydrolyze the sn-2 ester linkage of membrane phospholipids resulting in release of a free fatty acid and a lysophospholipid (see, Dennis, E. A., The Enzymes, Vol. 16, pp. 307-353, Boyer, P. D., ed., Academic Press, New York, 1983). Elevated levels of type II PLA.sub.2 are correlated with a number of human inflammatory diseases. The PLA.sub.2 -catalyzed reaction is the rate-limiting step in the release of a number of pro-inflammatory mediators. Arachidonic acid, a fatty acid commonly linked at the sn-2 position, serves as a precursor to leukotrienes, prostaglandins, lipoxins and thromboxanes. The lysophospholipid can be a precursor to platelet-activating factor. PLA.sub.2 is regulated by pro-inflammatory cytokines and, thus, occupies a central position in the inflammatory cascade (see, e.g., Dennis, ibid.; Glaser, et al., TiPs Reviews 1992, 14, 92; and Pruzanski, et al., Inflammation 1992, 16, 451).
All mammalian tissues evaluated thus far have exhibited PLA.sub.2 activity. At least three different types of PLA.sub.2 are found in humans: pancreatic (type I), synovial fluid (type II) and cytosolic. Studies suggest that additional isoenzymes exist. Type I and type II, the secreted forms of PLA.sub.2, share strong similarity with phospholipases isolated from the venom of snakes. The PLA.sub.2 enzymes are important for normal functions including digestion, cellular membrane remodeling and repair, and in mediation of the inflammatory response. Both cytosolic and type II enzymes are of interest as therapeutic targets. Increased levels of the type II PLA.sub.2 are correlated with a variety of inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and septic shock, suggesting that inhibitors of this enzyme would have therapeutic utility. Additional support for a role of PLA.sub.2 in promoting the pathophysiology observed in certain chronic inflammatory disorders was the observation that injection of type II PLA.sub.2 into the footpad of rats (Vishwanath, et al., Inflammation 1988, 12, 549) or into the articular space of rabbits (Bomalaski, et al., J. Immunol. 1991, 146, 3904) produced an inflammatory response. When the protein was denatured before injection, no inflammatory response was produced.
The type II PLA.sub.2 enzyme from synovial fluid is a relatively small molecule (about 14 kD) and can be distinguished from type I enzymes (e.g., pancreatic) by the sequence and pattern of its disulfide bonds. Both types of enzymes require calcium for activity. The crystal structures of secreted PLA.sub.2 enzymes from venom and pancreatic PLA.sub.2, with and without inhibitors, have been reported (Scott, et al., Science 1990, 250, 1541). Recently, the crystal structure of PLA.sub.2 from human synovial fluid has been solved (Wery, et al., Nature 1991, 352, 79). The structures clarify the role of calcium and amino acid residues in catalysis. The calcium acts as a Lewis acid to activate the scissile ester carbonyl and bind the lipid, and a His-Asp side chain dyad acts as general base catalyst to activate a water molecule nucleophile. This is consistent with the absence of any acyl enzyme intermediates, and is also comparable to the catalytic mechanism of serine
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Miyake, et al., "The
Acevedo Oscar L.
Cook Phillip Dan
Davis Peter W.
Ecker David J.
Hebert Normand
ISIS Pharmaceuticals Inc.
Marschel Ardin H.
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