Method for treating atherosclerosis employing an aP2 inhibitor and combination

Abstract

A method is provided for treating atherosclerosis and related diseases, employing an aP2 inhibitor or a combination of an aP2 inhibitor and another antiatheroscletotic agent, for example, an HMG CoA reductase inhibitor such as pravastatin.

1 . A method for treating atherosclerosis which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an aP2 inhibitor. 
     
     
         2 . The method as defined in  claim 1  wherein the aP2 inhibitor binds to the aP2 protein and inhibits its function and/or its ability to bind free fatty acids. 
     
     
         3 . The method as defined in  claim 1  wherein the aP2 inhibitor contains a hydrogen bond donator or acceptor group 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. 
     
     
         4 . The method as defined in  claim 3  wherein the hydrogen bond donator or acceptor group is acid in nature. 
     
     
         5 . The method as defined in  claim 3  wherein said aP2 inhibitor contains an additional substituent which 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. 
     
     
         6 . The method as defined in  claim 5  wherein said additional substituent in said aP2 inhibitor is hydrophobic in nature. 
     
     
         7 . The method as defined in  claim 5  in which the through space distance from the hydrogen bond donor/acceptor group and the additional substituent group in said aP2 inhibitor is within the distance of about 7 to about 15 Angstroms. 
     
     
         8 . The method as defined in  claim 1  wherein Type II diabetes is treated. 
     
     
         9 . The method as defined in  claim 1  wherein the aP2 inhibitor is employed in the form of a pharmaceutically acceptable salt thereof or a prodrug ester thereof. 
     
     
         10 . The method as defined in  claim 1  wherein the aP2 inhibitor includes an oxazole or analogous ring, a pyrimidine derivative or a pyridazinone derivative. 
     
     
         11 . The method as defined in  claim 10  wherein the aP2 inhibitor is a substituted benzoyl or biphenyl-2-oxazole-alkanoic acid derivative, an oxazole derivative, a 2-thio-4,5-diphenyloxazole S-derivative, a phenyl-heterocyclic oxazole derivative, a diaryloxazole derivative, a 4,5-diphenyloxazole derivative, an oxazole carboxylic acid derivative, a phenyloxazolyloxazole derivative, or a 2-(4,5-diaryl)-2-oxazolyl substituted phenoxyalkanoic acid derivative. 
     
     
         12 . The method as defined in  claim 10  wherein the aP2 inhibitor is a 2-benzyloxypyrimidine derivative, a dihydro(alkylthio)(naphthylmethyl)oxypyrimidine derivative, a thiouracil derivative, or an α-substituted pyrimidine-thioalkyl or alkyl ether derivative. 
     
     
         13 . The method as defined in  claim 10  wherein the aP2 inhibitor is a pyridazinone acetic acid derivative. 
     
     
         14 . A pharmaceutical combination comprising an aP2 inhibitor and another type antiatherosclerotic agent. 
     
     
         15 . The combination as defined in  claim 14  wherein the other antiatherosclerotic agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, other cholesterol lowering agent, a lipoxygenase inhibitor, an ACAT inhibitor or a PPAR α/γ agonist. 
     
     
         16 . The combination as defined in  claim 16  wherein the antiatherosclerotic agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin or fluvastatin. 
     
     
         17 . The combination as defined in  claim 16  wherein the aP2 inhibitor is present in a weight ratio to the antiatherosclerotic agent within the range from about 0.01 to about 100:1. 
     
     
         18 . A method for treating atherosclerosis which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in  claim 16 .