Arylsulfonamides as phospholipase A.sub.2 inhibitors

Details Arylsulfonamides as phospholipase A.sub.2 inhibitors Arylsulfonamides as phospholipase A.sub.2 inhibitors

1996-12-11

1999-11-30

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

514597, 514603, 558241, 560 12, 564 49, 564 86, A01N 4710, A01N 4728, C07C33300, C07C27300

Patent

active

059943980

ABSTRACT:
Arylsulfonamides which have the general structure: with the symbols R.sup.1, R.sup.2, R.sup.3, R.sup.4, A and n representing the groups and integers provided in the detailed description are provided herein. These compounds have activity as inhibitors of phospholipase A2, inhibitors of cytokine release and as inhibitors of neurodegeneration.

REFERENCES:
patent: 4666829 (1987-05-01), Glenner et al.
patent: 5137873 (1992-08-01), Yanker
patent: 5192753 (1993-03-01), McGeer et al.
patent: 5276059 (1994-01-01), Caughey et al.
patent: 5281626 (1994-01-01), Oinuma et al.
patent: 5322776 (1994-06-01), Knopf et al.
patent: 5328842 (1994-07-01), Chiou et al.
patent: 5354677 (1994-10-01), Knopf et al.
patent: 5453443 (1995-09-01), Perrier et al.
patent: 5466595 (1995-11-01), Jones et al.
patent: 5478857 (1995-12-01), Clemens et al.
patent: 5530118 (1996-06-01), Oinuma et al.
patent: 5554511 (1996-09-01), Jones et al.
patent: 5707821 (1998-01-01), Rydel et al.
patent: 5866318 (1999-02-01), Rydel et al.
Lalizari, et al., "Synthesis of new urethans. pCyclohexylsufamoyl and pPiperidinosulfonylcarbanilic acid esters," J. Med. Chem., 14(10):1017-1021 (1971).
Wadsworth, et al., "Synthetic applications of phosphoryl-stabilized anions," Org. React., 25:73-253 (1977).
Glenner, et al., "Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein," Biochem. Biophys. Res. Commun., 120(3):885-890 (May 16, 1984).
Martin, et al., "Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation," J. Cell Biol., 106:829-844 (1988).
Tanzi, R.E., "Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzeimer's disease," Nature, 331:528-530 (1988).
Ponte, et al., "A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors," Nature, 331:525-527 (1988).
Kitaguchi, et al., "Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity," Nature, 331: 530-532 (1988).
Neve, et al., "The Alzheimer amyloid precursor-related transcript lacking the .beta./A4 sequence is specifically increased in Alzheimer's disease brain," Neuron, 5:329-338 (Sep. 1990).
Yankner, et al., "Neurotrophic and neurotoxic effects of amyloid .beta. protein: reversal by tachykinin neuropeptides," Science, 250:279-282 (Oct. 12, 1990).
Kang, et al., "Differential splicing of Alzheimer's disease amyloid A4 precursor RNA in rat tissues: preA4.sub.695 mRNA is predominantly produced in rat and human brain," Biochem. Biophys. Res. Commun., 166(3):1192-1200 (Feb. 14, 1990).
Johnson, et al., "Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease," Science, 248:854-857 (May 18, 1990).
Clark, et al., "A novel arachidonic acid-selective cytosolic PLA.sub.2 contains a Ca.sup.2 -dependent translocation domain with homology to PKC and GAP," Cell, 65:1043-1051 (Jun. 14, 1991).
Oinuma, et al., "Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A.sub.2 inhibitors," J. Med. Chem., 34(7):2260-2267 (1991).
Sharp, et al., "Molecular cloning and expression of human Ca.sup.2+ -sensitive cytosolic phospholipase A.sub.2," J. Biol. Chem., 266(23):14850-14853 (1991).
Kowall, et al., "An in vivo model for the neurodegenerative effects of .beta. amyloid and protection by substance P," Proc. Natl. Acad. Sci. (USA)m 88L7247-7251 (Aug. 1991).
Yoshioka, et al., "The .sup.717 Val.fwdarw.Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups," BIochem. Biophys. Res. Commun., 178(3):1141-1146(Aug. 15, 1991).
Reynolds, et al., "Assay strategies and methods for phospholipases," Methods in Enzymology, 197:3-23 (1991).
Joel N. Buxbaum, "197. The amyloid diseases," 19th Edition: Cecil Textbook of Medicine, 1:1141-1145, W.B. Saunders, Philadelphia, PA (1992).
Hardy, et al., "Alzheimer's disease: The amyloid cascade hypothesis," Science, 256:184-185 (Apr. 10, 1992).
Seubert, et al., "Isolation and quantifiation of soluble ALzheimer's .beta.-peptide from biological fluids," Nature, 359:325-327(Sep. 24, 1992).
Lin, et al., "Cytosolic phospholipase A.sub.2 is coupled to hormonally regulated release of arachidonic acid," Proc. Natl. Acad. Sci. (USA), 89:6147-6151 (Jul. 1992).
Haass, et al., "Anyloid .beta.-peptide is produced by cultured cells during normal metabolism," Nature, 359:322-325 (Sep. 24, 1992).
Mattson, et al., ".beta.-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity," J. Neurosci., 12(2):376-389 (Feb. 1992).
Qiu, et al., "Regulation of phospholipase A.sub.2 activation by phosphorylation in mouse peritoneal macrophages," J. Biol. Chem., 268(32):24506-24513 (1993).
Kramer, et al., "Thrombin-induced phosphorylation and activation of Ca.sup.2+ -sensitive cytosolic phospholipase A.sub.2 in human platelets," J. Biol. CHem., 268(35)26796-26804 (Dec. 15, 1993).
Brewer, et al., "Optimized survival of hippocampal neurons in B27-supplemented neurobasal.TM., a new serum-free medium combination," J. Neurosci. Res., 35(5):567-576 (1993).
Street, et al., "Slow-and tight-binding inhibitors of the 85-kDa human phospholipase A.sub.2," Biochemistry, 32:5935-5940 (1993).
Verity, M.A., "Mechanisms of phospholipase A.sub.2 activation and neuronal injury," Ann. N.Y. Acad. Sci., 679:110 (1993).
Lin, et al., "cPLA.sub.2 is phosphorylated and activated by MAP kinase," Cell, 72:269-278 (Jan. 29, 1993).
Kramer, "Structure, function and regulation of mammalian phospholipases A.sub.2," Advances in Second Messenger and Phosphorprotein Research, 28:81-89 (1993).
Pike, et al., "Neurodegeneration induced by .beta.-amyloid peptides in vitro: The role of peptide assembly state," J. Neurosci., 13(4):1676-1687 (Apr. 1993).
Glaser, et al., "Phospholipase A.sub.2 enzymes: regulation and inhibition," TiPS, 14:92 (Mar. 1993).
Mattson, et al., ".beta.-Amyloid precursor protein metabolities and loss of neuronal Ca.sup.2+ homeostasis in Alzheimer's disease," Trends in Neuroscience, 16(10):409 (Oct. 1993).
Agarwal, et al., "Phospholipase activation triggers apoptosis in photosensitized mouse lymphoma cells," Cancer Res., 53:5897-5902 (Dec. 15, 1993).
Dumuis, et al., "Stimulation by glutamate receptors of arachidonic acid release depends on the Na.sup.+ /Ca.sup.2+ exchanger in neuronal cells," Mol. Pharmacol., 43:976-981 (Mar. 29, 1993).
Roshak, et al., "Suppression of monocyte 85-kDa phospholipase A.sub.2 by antisense and efects on endotoxin-induced prostaglandin biosynthesis," J. Biol. Chem., 269(42):25999-26005 (Oct. 21, 1994).
Reyolds, et al., "1-Hexadecyl-2-arachidonoylthio-2-deoxy-sn-glycero-3-phosphorylcholine as a substrate for the microtiterplate assay of human cytosolic phospholipase A.sub.2," Anal. Biochem., 217:25-32 (1994).
Currie, et al., "Phosphorylation and activation of Ca.sup.2+ -sensitive cytosolic phospholipase A.sub.2 in MCII mast cells mediated by high-affinity F.sub.c receptor for IgE," Biochem. J., 304:923-928 (1994).
Dennis, E.A., "DIversity of group types, regulation, and function of phospholipase A.sub.2," J. Biol. Chem., 269(18):13057-13060 (May 6, 1994).
Bartoli, et al., "Tight bonding inhibitors of 85-kDa phospholipase A.sub.2 but not 14-kDa phospholipase A.sub.2 inhibit release of free arachidonate in thrombin-stimulated human platelets," J. Biol. Chem., 269(22):15625-15630 (May 6, 1994).
Lorenzo, et al., ".beta.-Amyloid neurotoxicity requres fibril formation and is inhibited by Congo red," Proc. Natl. Acad. Sci. (USA), 91:12243-12247 (Dec. 1994).
Schubert, et al., "Amyloid peptides are toxic via a common oxidative mechanism," Proc. Natl. Acad. Sci. (USA), 92:1989-1993 (Mar. 1995).
Petit, et al., "Isolation and characterization of a cytosolic phospholipase A.sub.2 from bovine adrenal medulla," J. Neurochem., 64(1)139-146 (1995).
Meda, et al., "Activation of microglial cells by .beta.-amyloid protein and interferon-.gamma.," Nature, 374:647-650 (1995).
Ackermann

Affiliated with

Also associated with

Rating

Arylsulfonamides as phospholipase A.sub.2 inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Arylsulfonamides as phospholipase A.sub.2 inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Arylsulfonamides as phospholipase A.sub.2 inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1673322