Structure-activity relationships of (4-acylpyrrol-2-yl)alkanoic acids as inhibitors of the cytosolic phospholipase A2: variation of the substituents in positions 1, 3, and 5.
Derivatives of 3-(1,3,5-trimethyl-4-octadecanoylpyrrol-2-yl)propionic acid (1) and (1,3,5-trimethyl-4-octadecanoylpyrrol-2-yl)acetic acid (4) were prepared and evaluated for their ability to inhibit the cytosolic phospholipase A2 of intact bovine platelets. While replacement of one of the methyl groups in position 1, 3, or 5 of the acetic acid 4 by a benzyl residue did not influence the inhibitory potency significantly, the introduction of a dodecyl chain led to compounds which even enhanced the enzymatic activity. Stepwise elongation of the alkyl substituent in position 1 showed that the ability to inhibit the enzyme was lost when the alkyl chain exceeded a length of five carbons in case of compound 1 or six carbons in case of compound 4. Introduction of a polar functional group at the end of the 1-alkyl chain of these inactive pyrroles, however, restored or even elevated inhibitory potency. The most preferable of the polar terminal functions investigated was the carboxylic acid moiety. 6-[2-(2-Carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]hexanoi c acid (65c) and 6-[2-(carboxymethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]nonanoic acid (66f) were the synthesized inhibitors with the greatest potency. With IC50 values of 3.4 and 3.3 microM, respectively, they were about 3-fold more active than the standard cPLA2 inhibitor arachidonyl trifluoromethyl ketone (IC50: 11 microM).
Lehr
M
M
Institute of Pharmacy and Food Chemistry, Ludwig-Maximilians-University, Munich, Germany.
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007476:Ionophores / Q000494:pharmacology; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C108926:6-(2-(2-carboxyethyl)-4--dodecanoyl-3,5-dimethylpyrrol-1-yl)nonanoic acid; C108925:6-(2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl)hexanoic acid; D002208:Caproates; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007476:Ionophores; D011758:Pyrroles; D016718:Arachidonic Acid; D000001:Calcimycin; D010741:Phospholipases A; D054467:Phospholipases A2