Biomedical subjects

J J Godfroid

Publications and source records attributed to J J Godfroid.

At least 19 recordsLinked to original sources

PubMed1999

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.

Animals↗

PubMed1999

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline.

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2', 4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of alpha2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4', 5'-dihydro-1'H-imidazol-2'-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 micromol/kg) as after ip administration and appears as a good candidate for clinical investigations.

Animals↗

PubMed1999

In vitro mechanism of action on insulin release of S-22068, a new putative antidiabetic compound.

Adrenergic alpha-Antagonists↗

PubMed1998

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 (deltaG) and insulin (deltaI), 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)), deltaG (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, deltaI 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.

Animals↗

PubMed1997

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 1. Synthesis and biological activities of N-benzyl-N'-(arylalkyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines .

The physiopathology of non-insulin-dependent diabetes mellitus is associated with a dysfunction in the regulation of insulin secretion. The alpha 2-adrenoceptors have been reported to be involved in this alteration, although alpha 2-antagonists containing an imidazoline ring may stimulate insulin secretion independently of alpha 2-adrenoceptor blockage. Recently, a new "imidazoline-binding site" involved in the control of K(+)-ATP channels in the B cell has been proposed. In the course of searching for new antidiabetic agents, 1-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines, 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-alkylpiperazines, and 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines have been designed and evaluated as potential adrenoceptor antagonists. Pharmacological evaluation was performed in vivo using glucose tolerance tests performed on a rat model of type II diabetes obtained by injection of a low dose (35 mg/kg) of streptozotocin (STZ). For some compounds, binding experiments were performed on alpha 2 adrenoceptors and I1 and I2 imidazoline-binding sites. The biological and physicochemical data have been combined with molecular modeling studies to establish structure-activity relationships. The most active compound was 1-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)- 4-methylpiperazine (7f); intraperitoneal administration (100 mumol/kg) of 7f strongly improved glucose tolerance in STZ diabetic rats. This effect seemed at least partly mediated by a significant increase of insulin secretion. Other compounds of the same family (7b, 16f, 23b) have also shown potent activity. We found no correlation between in vivo antihyperglycemic properties and in vitro affinities for alpha 2-adrenoceptors or I1, and I2 binding sites. These compounds can be considered as antihyperglycemic agents potentially useful for treatment of type II diabetes and are currently under complementary investigation.

Animals↗

PubMed1997

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 IC50's 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.

Animals↗

PubMed1997

Design and modeling of new platelet-activating factor antagonists. 3. Relative importance of hydrophobicity and electronic distribution in piperazinic series.

Extensive analysis of results obtained in earlier publications (Lamouri et al. (1993); Tavet et al. (1996) led us to reexamine our interpretations and conclusions about hydrophobic and electronic distribution effects. In terms of hydrophobicity balance, a bilinear regression has been derived between lipophilicity of the appendix in position-2, f(Z), versus anti-aggregant activity for 45 homogeneous compounds including data from both papers (Parts 1 and 2). These features reinforce the conclusion that the kinetic phase in the experimental medium is probably determinant. Consequently, the role of electronic distribution is preponderant at the level of the receptor. Two specific studies demonstrated that decrease of negative electrostatic potential effects of the largest "cache-oreilles' system lowered the anti-aggregant activity (comparison of compounds 1f, 2, 3 and 4), on one hand and, on the other hand, the combined effect of phenyl groups created negative wells, as observed there with a diphenyl-methyl moiety, instead of an usual trimethoxybenzoyl function (comparison of compounds 8 and 10). It was clearly demonstrated that this moiety does not work by means of a hydrophobic anchorage: comparison of compounds 9, 10 and 11.

Chemical Phenomena↗

PubMed1997

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).

Animals↗

PubMed1997

Preventive effects of two PAF-antagonists, PMS 536 and PMS 549, on cyclosporin-induced LLC-PK1 oxidative injury.

The present study was undertaken to evaluate the effects of platelet activating factor (PAF) antagonists, PMS 536 and PMS 549, on LLC-PK1 toxicity induced by Cyclosporin A (CsA). The LLC-PK1 cell line was used as an in vitro model. CsA cytotoxicity was determined in relation with ATP content. Alkaline phosphatase and N-acetyl-beta-glucosaminidase activities, which are directly correlated with tubular cell damage, were used as markers for renal injury. CsA alone provoked in the LLC-PK1 cell line a marked decrease in cell viability (55%) and membrane integrity (56%), and a significant increase in AP and NAG activities and in oxidized glutathione level. The ATP decrease and the ADP increase, resulting in a decline of the ATP/ADP ratio, is indicative of an anoxic energy charge. Co-treatment with CsA plus PMS 536 or PMS 549 resulted in a minor decrease in cell viability and in significant membrane integrity recovery. Moreover, the ATP depletion and the increase in ATP metabolites, hypoxanthine and uric acid induced by CsA were strongly prevented by PAF antagonists. In contrast, GSSG level remained high as in CsA-treated cells, but GSH level was in the range of controls. Our results suggest that both PAF antagonists attenuate CsA oxidative injury and prevent energy metabolism disturbances probably by maintaining cell integrity. The lipophilicity of both molecules may be responsible for membrane stabilization and may confer the protective effects observed in energy metabolism. The results obtained with PMS 536 and PMS 549 are indicative of interactions between PAF and CsA in renal injury and suggest the therapeutic potential of these PAF-antagonists against CsA-induced nephrotoxicity.

Acetylglucosaminidase↗

PubMed1997

A new phospholipase A2 inhibitor, unrelated to substrate analogues: kinetic characterization of the inhibition of secretory phospholipases A2 by PMS 832.

Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA2s of groups I or II, with IC50 in the micromolar range (Binisti et al., 1997). In this report we investigate the mechanism of inhibition of bovine and porcine pancreatic phospholipases A2 (group I), and platelet lysate phospholipase A2 (group II) by one of these compounds, 1-(4'-methoxybenzoyl)-2-n-tridecylpiperazine (PMS 832). We show that PMS 832 behaves as a reversible, competitive inhibitor, with Ki values of 4.1 +/- 1.2 and 1.5 +/- 0.4 microM for porcine pancreatic phospholipase A2 and platelet lysate phospholipase A2, respectively. PMS 832 failed to inhibit platelet activation induced by several agonists and was also found to be inactive towards phospholipase C from Bacillus cereus, indicating a high specificity for phospholipase A2 inactivation. Thus, PMS 832 and its derivatives could serve as interesting tools to investigate the role of extracellular phospholipases A2 in inflammatory processes, and may be useful in the development of new anti-inflammatory agents.

Animals↗

PubMed1997

Stimulation of insulin release from the MIN6 cell line by a new imidazoline compound, S-21663: evidence for the existence of a novel imidazoline site in beta cells.

1. The MIN6 cell line derived from in vivo immortalized insulin-secreting pancreatic beta cells was used to study the insulin-releasing capacity and the cellular mode of action of S-21663, a newly synthesized imadizoline compound known for its antidiabetic effect in vivo and its ability to release insulin from perfused pancreas. 2. S-21663, at concentrations ranging from 10(-5) M to 10(-3) M was able to release insulin from MIN6 cells; its activity peaked at 10(-4) M, a drop in the stimulant factor being noted between 10(-4) and 10(-3) M. Its efficacy, which did not differ whatever the glucose concentration (stimulant or not), was higher than that of the other secretagogues tested, glucose, sulphonylureas or the peptide tGLP-1. 3. In contrast to tGLP-1, S-21663 did not change the cyclic AMP content, whereas it increased Ca2+ influx via verapamil- and nifedipine-sensitive voltage-dependent calcium channels, the insulin release being a direct consequence of this Ca2+ entry. The S-21663-induced Ca2+ influx appears to be essentially the consequence of closure of K+ channels which differ from the ATP-dependent K+ (K-ATP) channels as determined by measurement of 86Rb efflux and use of a K-ATP channel opener. 4. Comparison of the effects of S-21663 to that of efaroxan, another imidazoline compound shown to act on insulin release in a glucose-dependent way via binding sites distinct from the imidazoline I1 and I2 sites, suggested that S-21663 acts through a novel site which displays a remarkably stable expression along the cell culture. 5. It is concluded that S-21663 is a very efficient, glucose-independent insulin secretagogue acting through a novel imidazoline site, linked to K+ channels, distinct from the I1, I2 and 'efaroxan' binding sites. In vitro and in vivo features of S-21663 indicate that this compound, or new drugs derived from it, might be the basis for a new pharmacological approach to the mangement of type II (non insulin-dependent) diabetes.

Binding Sites↗

PubMed1996

4-Alkoxybenzamidines as new potent phospholipase A2 inhibitors.

A series of 4-alkoxybenzamidines was synthesized, varying the number of carbons of the alkyl chain, and their potency as phospholipase A2 (PLA2) inhibitors was evaluated. The relationship between their capacity to inhibit PLA2 activity and their lipophilicity was examined. The optimum of the inhibitory effect against two extracellular PLA2S from rabbit platelets and bovine pancreas was observed with compounds bearing an alkyl chain of 12 and 14 carbons. These 4-dodecyl and tetradecyloxbenzamidines inhibited bovine pancreatic and rabbit platelet lysate PLA2S with IC50 values of 3 microM and 5-5.8 microM, respectively. The mechanism of inhibition was of the competitive type. In addition, 4-tetradecyloxbenzamidine was shown to exert an antiinflammatory effect in vivo on the carrageenan-induced rat paw oedema. These results show that 4-tetradecyloxybenzamidine will serve as an interesting tool to investigate the physiological role of mammalian-secreted PLA2, both in vitro and in vivo.

Acute Disease↗

PubMed1996

Structure-activity relationships in platelet-activating factor (PAF). 7. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors. Synthesis and PAF-antagonistic activity.

2,5-Disubstituted tetrahydrofuran derivatives present a dual activity: they are effective PAF antagonists and acetylcholinesterase inhibitors. In this paper their synthesis and in vitro PAF-antagonistic effect are described. Introduction in position 2 of a long aliphatic chain bearing a carbamate group and a pyridinium moiety appears to be required for potent platelet aggregation inhibition. Substitution in position 5, or cis-trans isomerism do not induce any increase in activity. No correlation can be established between global lipophilicity and the anti-aggregant activity. Structural requirements for a potent activity are discussed and are consistent with the hypothesis we have proposed for the PAF receptor considered as a multipolarized structure with alternants of electropositive, electronegative and hydrophobic areas.

Carbamates↗

PubMed1996

Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < sigma f < 7) are the main features required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity.

Acetylcholinesterase↗

PubMed1996

Effect of S-21663 (PMS 812), an imidazoline derivative, on glucose tolerance and insulin secretion in a rat model of type II diabetes.

We have studied the activity of S-21663 (PMS 812), a new imidazoline derivative, in a rat model of Type II diabetes obtained by i.v. injection of a low dose (35 mg/kg) of streptozotocin, using glucose tolerance tests. Glucose tolerance and insulin secretion were measured as the delta G and the delta l, i.e., the respective increase in glycemia and insulinemia over 30 min after the glucose load. The rate of glucose disappearance was calculated as the K coefficient and the insulin response to glucose as the delta l/delta G. After i.p. injection of S-21663, delta G (millimoles per liter per minute) was decreased (71.7 +/- 10.1 vs. 112.6 +/- 15.1; P < .05), whereas K was increased (3.3 +/- 0.3 vs. 1.5 +/- 0.1; P < .05). Insulin secretion was also largely improved (delta l/delta G: 90.9 +/- 22.2 vs. 18.3 +/- 2.6; P < .05). Oral administration of the product was almost as efficient as i.p. injection. Chronic treatment (15 days) increased the efficiency. Insulin secretion measured in vitro at both 2.8 and 16.6 mM glucose was quadrupled by S-21663 (100 microM). S-21663 binds neither to alpha-2 adrenoceptors nor to known imidazoline binding sites. S-21663 can be considered as a potential hypoglycemic agent in Type II diabetes.

Animals↗

PubMed1993

Design and modeling of new platelet-activating factor antagonists. 1. Synthesis and biological activity of 1,4-bis(3',4',5'-trimethoxybenzoyl)-2-[[(substituted carbonyl and carbamoyl)oxy]methyl]piperazines.

To further investigate our hypothesis on the structure of the platelet-activating factor (PAF) receptor, 35 compounds derived from 1,4-bis(3',4',5'-trimethoxybenzoyl)piperazine were synthesized and their in vitro antagonistic effect was measured. Substitution of the compounds in position 2, by ester or carbamate groups, giving increased steric hindrance and hydrophobicity, increased the platelet aggregation inhibitory activity from 2 microM (without substitution, compound 2) to 0.07 microM (compound 1h) and gave a maximum displacement of [3H]PAF from platelet membrane of 0.05 microM (compound 1k). It appears that the PAF antagonistic effect is only weakly enantiospecific, as observed in many cases including antagonists structurally related or not to PAF. 3D electrostatic potential maps (calculated at -10 kcal/mol) of such compounds revealed a double "Cache-oreilles" (ear-muffs) system. One of these systems has been previously described (distance between atoms generating negative wells, 11-14 A). The second shorter "Cache-oreilles" (6-7 A) system appears to be required for increased PAF antagonistic activity. This short distance between groups generating the negative wells is present in the gingkolides, a series of naturally occurring PAF antagonists. The present study indicates that the structure of the PAF receptor may be more complicated than our initial hypothesis and may be a tetrapolarized structure, with alternants of electropositive and hydrophobic areas. This modified hypothesis is in agreement with recent publications concerning PAF antagonists bearing a cationic moiety.

Animals↗

PubMed1992

Production and characterization of antibodies to platelet-activating factor.

Antibodies directed against platelet-activating factor (PAF) have been raised in rabbits immunized with a novel platelet-activating factor analogue-conjugate. An analogue of PAF with a carbon double bond at the terminal end of the alkyl chain was subjected to ozonolysis and converted to the aldehyde. The aldehyde was coupled to thyroglobulin by reductive alkylation and rabbits were immunized via either intramuscular or intradermal routes in complete Freund's adjuvant. The antibodies are specific for PAF with a preference for the optically active (R)-enantiomer. There appears to be a requirement for antibody binding of an alkyl chain of up to 18 Carbon atoms at C1, and an acetyl group in the C2 position. The ability of a number of structural analogues to inhibit binding of tracer to the antibody is related to the biological activity of the analogue, and therefore may reflect the structural domains that are critical for PAF to interact with its receptor.

Animals↗

PubMed1992

Structure-activity relationships in platelet-activating factor (PAF antagonists). 6. Synthesis and in vitro antagonistic activities of 2-substituted 5-oxotetrahydrofurans.

The synthesis of 2,5-disubstituted tetrahedrofuran compounds as potential in vitro PAF antagonists is described. Results demonstrate that the structural requirements for potent PAF antagonist activity are: a moderate lipophilic group or a trimethoxyphenyl group in position-5, and a long aliphatic chain terminated by a cationic polar head in position-2. The cis-trans configuration does not induce any difference in biological activity. Some conformational features of the putative PAF receptor are proposed in light of the present findings.

Animals↗