Estera Touboul

Structure–activity relationships in platelet-activating factor (PAF). 11-From PAF-antagonism to phospholipase A2 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.

Potent antihyperglycaemic property of a new imidazoline derivative S-22068 (PMS 847) in a rat model of NIDDM

Recent data suggest that some imidazoline derivatives can lower plasma glucose in experimental animal models of diabetes. We studied the activity of an imidazoline S‐22068, in rat model of non‐insulin‐dependent diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg−1, i.v.) in the adult. The respective increase over basal value in glucose (ΔG) and insulin (ΔI), and the rate of glucose disappearance (K), were measured during a 30 min intravenous glucose tolerance test. After an intraperitoneal injection of S‐22068 (24 mg kg−1), ΔG (mM min −1) was decreased (91.67±5.83 vs 120.5±3.65; P<0.001), whereas K was increased (1.74±0.09 vs 1.18±0.05; P<0.001). Although insulinaemia was increased at time‐point 0 of the test, ΔI was unchanged. During oral glucose tolerance tests (OGTT), S‐22068 (24 mg kg−1, p.o.) improved glucose tolerance, and its efficiency was potentiated after chronic treatment (15 days). Basal glycaemia was unaffected by the treatment. Under the same conditions, a higher dose of S‐22068 (40 mg kg−1) further improved glucose tolerance without causing hypoglycaemia. Binding experiments revealed that S‐22068 displays no affinity for either adrenoceptors or the two imidazoline receptors I1 or I2. These results demonstrate that S‐22068 improves glucose tolerance without causing hypoglycaemia. Thus S‐22068 represents a new potential option in the treatment of NIDDM.

Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats

We have investigated the possible mechanisms underlying the antihyperglycaemic effect of the imidazoline derivative S-22068. In vitro, in the presence of 5 mmol/l glucose, S-22068 (100 micromol/l) induced a significant and sustained increase in insulin secretion from isolated, perifused, rat islets and a marked sensitization to a subsequent glucose challenge (10 mmol/l). S-22068 (100 micromol/l was able to antagonize the stimulatory effect of diazoxide on 86Rb efflux from preloaded islets incubated in the presence of 20 mmol/l glucose. Experiments were also performed to investigate whether S-22068 can alter glucose turnover and peripheral insulin sensitivity in vivo in mildly diabetic rats and obese, insulin resistant, Zucker rats. Neither glucose production nor individual tissue glucose utilization was modified by S-22068 in either group of rats. Similar results were obtained whether the studies were performed under basal conditions or during euglycaemic/hyperinsulinemic clamps. The results suggest that S-22068 exerts part of its antihyperglycaemic effect by promoting insulin secretion without alteration of peripheral insulin sensitivity.

Structure-activity relationships in platelet activating factor. 9. From PAF-antagonism to PLA2 inhibition

Many important mediators of inflammation result from the liberation of free arachidonic acid from phospholipid pools, which arise from the action of phospholipase A2 (PLA2). Therefore the inhibition of this enzyme would be an important treatment in many inflammatory disease states. Starting from a series of compounds which are known as PAF-antagonists, we have synthesized new molecules. These new compounds inhibited various secretory PLA2s, with IC50s in the mumol range. This allowed us to analyze the structure-activity relationships for PLA2 inhibition. The results showed that inhibition of secretory PLA2 depends on the length of the alkyl chain, with an optimum for 13 to 17 carbons, which is in agreement with X-ray crystallographic and nuclear magnetic resonance (NMR) studies on the active site of PLA2s, and that a free nitrogen on the piperazine ring is required to ensure a good inhibitory potency.

Design and modeling of new platelet-activating factor antagonists. 2. Synthesis and biological activity of 1,4-bis-(3′,4′,5′-trimethoxybenzoyl)-2-alkyl and 2-alkyloxymethylpiperazines☆

In the continuation of our investigations on the structure of platelet-activating factor (PAF)-receptor, 25 additional 2-substituted 1,4-bis-(poly- and mono methoxybenzoyl)-piperazines were synthesized and their in vitro biological activities measured. Substituent at position 2 is representative of the classical balance lipophilicity/hydrophilicity, i.e. alkyl, phenylalkyl, alkoxy and polyalkoxy groups. A potent PAF-induced platelet aggregation inhibitory activity measured in PRP medium is obtained with 5c, IC50 = 6 x 10(-8) M, which displaces the [3H]PAF from platelet membrane with an EC50 = 6 x 10(-8) M, and compound 4 presents an EC50 of 3 x 10(-8) M. Examination of structure-activity relationships shows that molecules bearing a hydrophilic or slightly hydrophobic appendix in position-2 are still potent; their IC50 being included between 10(-6) and 10(-7) M. After quantitative analysis, it seems that in PRP medium, the role of serum albumin must be taken into account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a potent antagonistic activity is demonstrated by syntheses of several 2-octylpiperazine analogs. These specific features will be quantitatively analysed in the following related publication (part 3).