ABSTRACT
The group IIA human non-pancreatic secretory phospholipase A(2) (hnp-sPLA(2)) is one of the enzymes implied in the inflammatory process. In the course of our work on inhibitors of this enzyme we investigated the influence of rigidity of the piperazine region on the biological activity. Several modifications were explored. Various linkers, such as amide, urea, carbamate, or alkoxyphenyl were inserted between the piperazine and the lipophilic chain. Also, modification of the piperazine core to incorporate carbonyl groups was studied. In an in vitro fluorimetric assay using the human GIIA (HPLA(2)) and porcine pancreatic GIB enzymes, compound 60a (Y=phenoxy, R=C(18)H(37), Z=CH(2)) had the optimal activity with an IC(50)=30nM on HPLA(2). By means of molecular modelling we attempted to get informations towards comprehension of differences in activity.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Phospholipases A/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Animals , CHO Cells , Cell Line , Combinatorial Chemistry Techniques , Cricetinae , Cricetulus , Enzyme Inhibitors/pharmacology , Humans , Piperazine , Quantitative Structure-Activity Relationship , Structure-Activity RelationshipABSTRACT
Starting from 4-tetradecyloxybenzamidine (PMS815), a non-specific inhibitor of GI and GII PLA2s, we report in this work the discovery of the specificity through design, synthesis and structure-activity relationships studies of different kinds of PMS815 derivatives. The leading compound, 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one (9b, PMS1062) exhibits a micromolar IC50 towards three group II PLA2s, while inactive towards four group I and one group III enzymes in two in vitro enzymatic assay conditions. It is also able to block the PLA2-II activities induced by LPS and IL-6 in HepG2 cell line and no cytotoxicity is observed when PMS1062 is tested up to a concentration of 100 microM in two different cell lines (A549 and LLC-PK1).
Subject(s)
Benzamidines/chemistry , Benzamidines/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Phospholipases A/antagonists & inhibitors , Animals , Benzamidines/chemical synthesis , Blood Platelets/enzymology , Cell Line , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Group II Phospholipases A2 , Humans , Inhibitory Concentration 50 , Molecular Structure , Oxadiazoles/chemistry , Pancreas/enzymology , Phospholipases A2 , Structure-Activity Relationship , Swine , Tetrazoles/chemistryABSTRACT
We have recently reported the discovery of a series of specific inhibitors of human group IIA phospholipase A(2) (hGIIA PLA(2)) to display promising in vitro and in vivo properties. Here we describe the influence of different structural modifications on the specificity and potency against hGIIA PLA(2) versus porcine group IB PLA(2). The SAR results, as well as the logP and pK(a) values of oxadiazolone determined in this work, provide important information towards the comprehension of the mode of action of this kind of compounds.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Phospholipases A/antagonists & inhibitors , Phospholipases A/metabolism , Alkylation , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Molecular Structure , Oxazoles/chemical synthesis , Phospholipases A/classification , Phospholipases A2 , Structure-Activity RelationshipABSTRACT
A new synthesis of attenol A is described. Key features of this work include a crucial silicon tether-aided coupling metathesis step and the use of iodoetherification as an efficient protection method for 1,5-ene-ols. [reaction: see text]
