Structure-activity relationships in platelet-activating factor (PAF). 11-From PAF-antagonism to phospholipase A(2) inhibition: syntheses and structure-activity relationships in 1-arylsulfamido-2-alkylpiperazines.
1-Benzoyl-2-alkyl piperazines are strong inhibitors of Group I and II secreted PLA(2)s. An improvement of their activity was obtained by replacing the amide function by a sulfamide and by introduction of electrodonor substituents on the para position of the benzenesulfonyl moiety. Neither the position on one of the carbon of the piperazine ring nor the absolute configuration of this carbon have an effect on the affinity for one or the other group of PLA(2), but the lipophilicity remains for these series an essential parameter. In addition structure-activity relationships allow new hypothesis on interaction of these piperazine derivatives with the catalytic site of PLA(2)s.
Binisti
C
C
Laboratoire de Pharmacochimie Moléculaire, Université Paris 7-Denis Diderot, 2 Place Jussieu, F-75251 cedex 05, Paris, France.
Assogba
L
L
Touboul
E
E
Mounier
C
C
Huet
J
J
Ombetta
J E
JE
Dong
C Z
CZ
Redeuilh
C
C
Heymans
F
F
Godfroid
J J
JJ
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000737:chemistry; D020134:Catalytic Domain / Q000187:drug effects; D002417:Cattle; D002614:Chelating Agents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D010972:Platelet Activating Factor; D013449:Sulfonamides; D010741:Phospholipases A; D002118:Calcium