Lipoprotein associated phospholipase A.sub.2, inhibitors thereof

Details Lipoprotein associated phospholipase A.sub.2, inhibitors thereof Lipoprotein associated phospholipase A.sub.2, inhibitors thereof

1995-02-24

1999-11-09

Sisson, Bradley L.

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

536 232, C12N 920, C07H 2104

Patent

active

059812524

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of inhibitors of an enzyme in the therapy, in particular in the treatment of atherosclerosis. The present invention also relates to the isolation and purification of the enzyme, to isolated nucleic acids encoding the enzyme, to recombinant host cells transformed with DNA encoding the enzyme, to the use of the enzyme in diagnosing a patient's susceptibility to atherosclerosis, and to the use of the enzyme in identifying compounds which are potentially useful for the treatment of atherosclerosis.
Lipoprotein Associated Phospholipase A.sub.2 (Lp-PLA.sub.2), also previously known in the art as Platelet Activating Factor Acetyl Hydrolase (PAF acetyl hydrolase). During the conversion of LDL to its oxidised form, Lp-PLA.sub.2 is responsible for hydrolysing the sn-2 ester of oxidatively modified phosphatidylcholine to give lyso-phosphatidylcholine and an oxidatively modified fatty acid. Both of these products of Lp-PLA.sub.2 action are potent chemoattractants for circulating monocytes. As such, this enzyme is thought to be responsible for the accumulation of cells loaded with cholesterol ester in the arteries, causing the characteristic `fatty streak` associated with the early stages of atherosclerosis. Inhibition of the Lp-PLA.sub.2 enzyme would therefore be expected to stop the build up of this fatty streak (by inhibition of the formation of lysophosphatidylcholine), and so be useful in the treatment of atherosclerosis. In addition, it is proposed that Lp-PLA.sub.2 plays a direct role in LDL oxidation. This is due to the poly unsaturated fatty acid-derived lipid peroxide products of Lp-PLA.sub.2 action contributing to and enhancing the overall oxidative process. In keeping with this idea, Lp-PLA.sub.2 inhibitors inhibit LDL oxidation. Lp-PLA.sub.2 inhibitors may therefore have a general application in any disorder that involves lipid peroxidation in conjunction with the enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes other conditions such as rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.
The present invention therefore provides in a first aspect an inhibitor of the enzyme lipoprotein associated Lp-PLA.sub.2 for use in therapy, in particular in the treatment of atherosclerosis. Suitable compounds able to inhibit the Lp-PLA.sub.2 enzyme are known in the art and include for example, the following compounds of structure (I): ##STR1## which R is C.sub.1-6 alkylCONR.sup.2 ; R.sup.2 is hydrogen or C.sub.1-6 alkyl; S(R.sup.3).sub.2, in which each group R.sup.3 is the same or different and is C.sub.1-6 alkyl, OR.sup.2, C.sub.1-4 alkanoyl, imidazolyl or N-methylimidazolyl hydrogen. alkyl .sup..sym. S(R.sup.3).sub.2, in which each group R.sup.3 is the same or different and is C.sub.1-6 alkyl, OR.sup.2, C.sub.1-4 alkanoyl, imidazolyl or N-methylimidazolyl; preferably Z is SR.sup.3 in which R.sup.3 is methyl or OR.sup.2 in which R.sup.2 is hydrogen
The compounds of structure (I) can be prepared by processes known to those skilled in the art, for example as described in J Chem Soc Chem Comm., 1993, 70-72; J Org Chem, 1983, 48, 1197 and Chem Phys Lipids, 1984,35,29-37 or procedures analogous thereto.
When used in therapy, the compounds of structure (I) are formulated in accordance with standard pharmaceutical practice.
The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and, lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing so

REFERENCES:
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patent: 5641669 (1997-06-01), Cousens et al.
U.T. Kim, et al., "Synthesis of Phospholipid Headgroups via Nucleophilic Ring Opening of 1.3.2-Dioxaphospholanes", J. Chem. Soc., Chem. Commun., pp. 70-71 (1993).
N. S. Chandrakumar. et al., "Stereospecific Synthesis of Ehter Phospholipids. Preparation of 1-Alkyl-2-(acylamino)-2-deoxyglycerophosphorylcholines", J. Org. Chem, pp. 1197-1202 (1983).
M.M. Ponpipom, et al., "Synthesis of Azide and Amide Analogs of Platelet-Activating Factor and Related Derivatives", Chem. Phys. Lipids, 35, pp. 29-37 (1984).
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