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Method for treating atherosclerosis employing an ap2 inhibitor and combination

Method for treating atherosclerosis employing an ap2 inhibitor and combination description/claims

The present invention relates to a method for treating atherosclerosis and related diseases, employing an aP2 inhibitor alone or in combination with another type antiatherosclerotic agent.

Fatty acid binding proteins (FABPs) are small cytoplasmic proteins which bind to fatty acids such as oleic acids which are important metabolic fuels and cellular regulators. Dysregulation of fatty acid metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes).

aP2, an abundant 14.6 KDa cytosolic protein in adipocytes, and one of a family of homologous intracellular fatty acid binding proteins (FABPs), is involved in the regulation of fatty acid trafficking in adipocytes and mediates fatty acid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report that aP2-deficient mice placed on a high fat diet for several weeks developed dietary obesity, but, unlike control-mice on a similar diet, did not develop insulin resistance or diabetes. Hotamisligil et al conclude that “aP2 is central to the pathway that links obesity to insulin resistance” (Abstract, page 1377).

DIALOG ALERT DBDR928 dates Jan. 2, 1997, Pharmaprojects No. 5149 (Knight-Ridder Information) discloses that a major drug company “is using virtual screening techniques to identify potential new antidiabetic compounds.” It is reported that “the company is screening using aP2, a protein related to adipocyte fatty acid binding protein.”

In accordance with the present invention, a method is provided for treating atherosclerosis wherein a therapeutically effective amount of a drug which inhibits aP2 (aP2 inhibitor) is administered to a human patient in need of treatment.

In addition, in accordance with the present invention, a method is provided for treating atherosclerosis, wherein a therapeutically effective amount of a combination of an aP2 inhibitor and another type of antiatherosclerotic agent is administered to a human patient in need of treatment.

Furthermore, in accordance with the present invention, a novel antiatherosclerotic combination is provided which is formed of a drug which inhibits aP2 and an antiatherosclerotic agent which functions by a mechanism other than by inhibiting aP2. The aP2 inhibitor will be employed in a weight ratio to the antiatherosclerotic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 10:1.

It will be appreciated that the method of the invention for treating atherosclerosis employing an aP2 inhibitor alone or in combination with an antiatherosclerotic agent encompasses treating, reducing risk of, inhibiting, preventing and/or reducing or causing regression of atherosclerosis.

The method of the invention also encompasses preventing, inhibiting or reducing risk of cardiovascular and cerebrovascular diseases resulting from atherosclerosis, such as cardiac and/or cerebral ischemia, myocardial infarction, angina, peripheral vascular disease and stroke.

The aP2 inhibitors suitable for use in the method of the invention are compounds which bind to the aP2 protein and inhibits its function and/or its ability to bind free fatty acids. The compounds will preferably contain less than 60 carbon atoms, more preferably less than 45 carbon atoms, and will contain less than 20 heteroatoms, more preferably less than 12 heteroatoms. They contain a hydrogen bond donator or acceptor group, preferably acidic in nature, which includes, but is not limited to, CO2H, tetrazole, SO3H, PO3H, P(R)(O)OH (where R is lower alkyl or lower alkoxy), OH, NHSO2R′ or CONHSO2R′ (where R′ is lower alkyl), and thiazolidindione, and interacts (directly or through an intervening water molecule), either by ionic or hydrogen bonding interactions, with one, two, or three of the three amino acid residues, designated as Arg 106, Arg 126 and Tyr 128 in human aP2, within the aP2 protein.

The compounds suitable for use herein preferably contain an additional substituent, preferably hydrophobic in nature, which include the following groups: alkyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, benzo-fused aryl and heteroaryl, and their substituted counterparts. Especially preferred are aryl and substituted aryl groups. More especially preferred is phenyl and halo or methyl substituted phenyl.

The hydrophobic substituent binds to (in) and/or interacts with a discrete pocket within the aP2 protein defined roughly by the amino acid residues Phe 16, Tyr 19, Met 20, Val 23, Val 25, Ala 33, Phe 57, Thr 74, Ala 75, Asp 76, Arg 78 in human aP2. The through space distance from the hydrogen bond donor/acceptor group and the additional substituent group is within the distance of about 7 to about 15 Angstroms.

The above compounds may be employed in the form of pharmaceutically acceptable salts thereof and prodrug esters thereof.

The term “antiatherosclerotic agent” as employed herein refers to antihyperlipidemic agents including HMG CoA reductase inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, fibric acid derivatives, squalene synthetase inhibitors and other known cholesterol lowering agents, lipoxygenase inhibitors, ACAT inhibitors, and PPAR α/γ dual agonists as disclosed hereinafter.

The accompanying FIGURE is a computer generated image of a partial X-ray structure of compound XVIA (described hereinafter) bound to human aP2.

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