# US 5,707,821 A · Identification of phospholipase A2 inhibitors in A.beta. peptide-mediated neurodegenerative disease

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- Number: US 5,707,821 A
- Document ID: US5707821A
- Status: Granted
- Kind: A
- Application number: 08/476,464
- Filed: 1995-06-07
- Granted: 1998-01-13
- Earliest claimed: 1995-06-07
- Assignees: Athena Neurosciences, Inc.
- Inventors: Russell E. Rydel; Michael S. Dappen
- Web page: https://patentgrep.com/patent/US5707821A

## CPC

- G01N 33/5058: {Neurological cells}
- A61K 31/63: Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- C07C 311/39: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C 323/52: the carbon skeleton being acyclic and saturated
- C07D 209/24: with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
- C07D 213/56: Amides
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 277/30: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 307/54: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/28: Halogen atoms
- C07D 333/60: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07F 9/4006: {Esters of acyclic acids which can have further substituents on alkyl}
- C12Q 1/34: involving hydrolase
- G01N 33/5008: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics}
- G01N 33/5014: {for testing toxicity}
- G01N 33/502: {for testing non-proliferative effects}
- G01N 33/5044: {involving specific cell types}
- C07C 2601/18: with a ring being at least seven-membered
- G01N 2333/918: Carboxylic ester hydrolases (3.1.1)
- G01N 2500/00: Screening for compounds of potential therapeutic value
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The invention provides methods and compositions for treating neurodegeneration in mammalian cells by administering a phospholipase A2 inhibitor.

## Claims

### Claim 1

A method for identifying active agents which inhibit neuronal degeneration induced by A.beta. peptide, comprising
administering an agent to a cell population consisting essentially of neurons or cells from neuronal cell lines, wherein said cell population is exposed to an amount of pathogenic amyloid .beta.("A.beta.") peptide that induces neuronal degeneration in the cell population,
determining whether the agent produces a detectable reduction in the amount and/or rate of neuronal degeneration in the cell population; and
determining whether the agent produces inhibition of phospholipase A2 "PLA.sub.2 " activity;
whereby if the agent produces inhibition of PLA.sub.2 activity and inhibits neuronal degeneration, the agent is thereby identified as an active agent.

### Claim 2 (depends on 1)

The method according to claim 1, wherein determining whether the agent produces inhibition of PLA.sub.2 activity is performed by in vitro assay using a predetermined quantity of PLA.sub.2 enzyme.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the PLA.sub.2 is produced by expression of a recombinant expression vector encoding human cytoplasmic phospholipase A2 "cPLA.sub.2 " in a host cell.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the cell population consists essentially of neurons or cells from neuronal cell lines of human or rodent origin.

### Claim 5 (depends on 1)

The method of claim 1, wherein the pathogenic amyloid .beta. peptide comprises an amyloid .beta. peptide having amino acids 25-35 of A.beta.1-40 (SEQ ID NO:2).

### Claim 6 (depends on 5)

The method of claim 5, wherein the pathogenic amyloid .beta. peptide is A.beta.1-40 (SEQ ID NO:2) or A.beta.1-42 (SEQ ID NO:1).

### Claim 7 (depends on 1)

The method of claim 1, wherein determining whether the agent produces inhibition of PLA.sub.2 activity comprises determining whether the presence of said agent produces inhibition of cPLA.sub.2 activity.