2-oxamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudopeptides
The disclosure provides a series of 2-oxoamides based on dipeptides and pseudodipeptides, which were synthesized and their activities toward two human intracellular phospholipases A2 (GIVA CPLA 2 and GVIA 1PLA 2) and one human secretory phospholipase A2 (GV sPLA 2) were evaluated. Derivatives containing a free carboxyl group are selective GIVA cPLA 2 inhibitors. A derivative based on the ethyl ester of an ether pseudodipeptide is the first 2-oxoamide, which preferentially inhibits GVIA iPLA 2. The effect of 2-oxoamides on the generation of arachidonic acid from RAW 264.7 macrophages was also studied. It was found that selective GIVA cPLA 2 inhibitors preferentially inhibited cellular arachidonic acid release; in which one pseudodipeptide gave an IC50 value of 2 μM.
1. A compound selected from the group consisting of:
a compound having the structural formula
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X is CH 2 , O, NH or N(C 1 -C 6 )alkyl;
Y and Z form CONH or CH 2 O;
R 1 and R 2 are each independently hydrogen, a side chain of a natural amino acid, a linear, branched or cyclic alkyl, a linear, branched or cyclic alkenyl, a linear, branched or cyclic alkynyl, or substituted or unsubstituted aryl;
R 3 is hydrogen or (C 1 -C 1 )alkyl;
the Activated Carbonyl Group is
and a compound having the structural formula
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X is CH 2 , O, NH or N(C 1 -C 6 )alkyl;
Y and Z form CONH or CH 2 O;
R 1 is hydrogen, a side chain of a natural amino acid, a linear, branched or cyclic alkyl, a linear, branched or cyclic alkenyl, a linear, branched or cyclic alkynyl, or substituted or unsubstituted aryl;
R 3 is hydrogen or (C 1 -C 6 )alkyl, and
R 4 is a linear, branched or cyclic alkyl, a linear, branched or cyclic alkenyl, a linear, branched or cyclic alkynyl, or substituted or unsubstituted aryl.
2. A pharmaceutical composition for use in inhibiting the enzymatic activity of phospholipase A 2 in a cell or organism, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
3. The pharmaceutical composition according to claim 2 , wherein the enzymatic activity inhibited is of phospholipase cPLA 2 , iPLA 2 or sPLA 2 .
4. The pharmaceutical composition according to claim 1 , wherein the compound is
5. A compound of structural formula:
6. The pharmaceutical composition of claim 2 , wherein the composition further inhibits cellular release of arachidonic acid.
7. A method for modulating the effects of inflammatory processes in a mammal, comprising administering an effective amount of the compound of claim 1 .
8. The method according to claim 7 , wherein the mammal is a human.
9. A method of inhibiting the enzymatic activity of phospholipase A 2 in a cell or organism, comprising contacting the cell or organism with a compound of claim 5 .