Biomedical subjects

J Forn

Publications and source records attributed to J Forn.

At least 19 recordsLinked to original sources

PubMed2004

Effect of chronic lithium treatment on the turnover of alpha2-adrenoceptors after chemical inactivation in rats.

One of the most effective psychotherapeutic agents in the treatment of bipolar disease is lithium. Chronic lithium treatment affects some signal transduction mechanisms such as cAMP, cGMP, inositol 1,4,5 P(3), Gi protein, protein kinase C and can also modify gene expression in rat brain. In a previous study, we observed a greater inhibitory effect of lithium on cAMP production after blockade of alpha(2)-adrenoceptors in rat cerebral cortex. Here we examine the influence of chronic lithium treatment on turnover of alpha(2)-adrenoceptors after their inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in rat cerebral cortex. After treatment with lithium for 10 days (120 mg/kg/day, i.p.), there was a significant increase in the appearance and disappearance rate constants of these adrenoceptors and a significant reduction of their half-life. These results suggest that chronic lithium administration alters the alpha(2)-adrenoceptor turnover in rat brain.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed2003

Effects of phospholipid vesicles (liposomes) on cAMP levels in the rat cerebral cortex.

We studied the effects of two types of liposomes (cholate-free liposomes and cholate-containing liposomes) on control (in the presence of 3-isobutyl-1 methyl xanthine [IBMX], a phosphodiesterase inhibitor) and stimulated (IBMX plus isoprenaline) cyclic 3',5'-adenosine monophosphate (cAMP) accumulation in slices of rat cerebral cortex. Our purpose was to examine whether or not liposomes with different lipid constituents modify levels of cAMP in vitro. Liposomes at low concentrations had a significant inhibitory effect on cAMP accumulation in brain tissue. This inhibition was concentration-dependent. Cholate-containing liposomes had a greater inhibitory effect at higher concentrations. Liposomes also inhibited cAMP accumulation in a dose-dependent manner when the tissues were preincubated with ouabain, a Na(+)-K(+)-ATPase inhibitor. These results demonstrate that, in rat brain, liposomes alone modified important biochemical responses such as the adenylyl cyclase-cAMP system coupled to beta-adrenoceptors. The significance of these findings for the mechanism of the action of liposomes is discussed.

1-Methyl-3-isobutylxanthine↗

PubMed2001

Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity.

This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.

Amines↗

PubMed2001

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Animals↗

PubMed1999

Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid.

The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.

Animals↗

PubMed1998

New azole antifungals. 2. Synthesis and antifungal activity of heterocyclecarboxamide derivatives of 3-amino-2-aryl-1-azolyl-2-butanol.

A series of 92 azole antifungals containing an amido alcohol unit was synthesized. The nature and substitution of the amide portion was systematically modified in search of improved antifungal activity, especially against filamentous fungi. The compounds were tested in vitro against a variety of clinically important pathogens and in vivo (po) in a murine candidosis model. Thiazole and thiophene carboxamides carrying both a substituted phenyl ring and a small alkyl group were best suited for activity against filamentous fungi. In a subset of these compounds, the amide portion was conformationally locked by means of a pyrimidone ring and it was proven that only an orthogonal orientation of the phenyl ring yields bioactive products. A tendency to display long plasma elimination half-lives was observed in both series. Two compounds, 74 and 107, representative of the open and cyclic amides, respectively, were chosen for further studies, based on their excellent activity in in vivo murine models of candidosis and aspergillosis. This work describes the SARs found within this series. The next paper displays the results obtained in a related series of compounds, the quinazolinones.

Animals↗

PubMed1998

New azole antifungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones.

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.

Animals↗

PubMed1998

Absorption and excretion of radioactivity after intravaginal administration of an advanced delivery system of 14C-flutrimazole vaginal cream to postmenopausal women.

In order to improve the effectiveness of treatment of vaginal yeast infections, flutrimazole, (CAS 119006-77-8), a broad spectrum local imidazolic fungicide, has been formulated in an advanced delivery system (Site Release, here in after briefly referred to as SR) designed to improve vaginal retention of the drug. To determine the extent of absorption of 14C-flutrimazole from this formulation, the absorption and excretion of total radioactivity have been studied in healthy postmenopausal female volunteers after intravaginal administration of approximately 5 g of SR Vaginal Cream containing 2% 14C-flutrimazole. Concentrations of unchanged flutrimazole have also been measured in plasma and urine, using a validated gas chromatography-mass spectrometry method. The rate of absorption was slow, with a mean peak plasma radioactivity concentration, Cmax, of 56 ng equivalents/ml, achieved at a mean Tmax of 28 h. Corresponding parameters for flutrimazole were 1.94 ng/ml at 24 h. At 24 h post-dose, unchanged flutrimazole represented only 3% of plasma total radioactivity which indicates that flutrimazole is extensively metabolised in man. Total radioactivity and unchanged flutrimazole were eliminated from plasma with terminal half-lives of 37 and 22 h, respectively. From the proportion of the radioactive dose excreted in urine and faeces, the maximal extent of absorption indicated for the intravaginal dose was about 8%, which is similar to that observed with other imidazolic compounds administered by this route. Thus, the formulation achieves the aim of prolonged drug action through the maintenance of therapeutic concentrations of the drug at the site of infection without notably increased absorption.

Absorption↗

PubMed1997

Synthesis and structure-activity relationship of a new series of potent AT1 selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles.

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

Angiotensin I↗

PubMed1997

Effect of endotoxin and platelet-activating factor on rat vascular permeability: role of vasoactive mediators.

The contribution of several vasoactive mediators such as histamine, serotonin, bradykinin, arachidonic acid metabolites and PAF to vascular permeability changes was determined in a rat model of acute endotoxemia. Lipopolysaccharide (10-40 mg/kg, i.v.) from E. coli 0127:B8 (LPS) elicited an increase in Evans blue extravasation in trachea, thymus, seminal vesicle and stomach, whereas other organs remained unaffected. LPS (25 mg/kg)-induced extravasation was not inhibited by intravenous pretreatment with histamine (H1) antagonist mepyramine (5 mg/kg) or bradykinin (B2) antagonist HOE-140 (0.1 mg/kg), whereas other standard drugs selectively inhibited leakage in particular tissues, e.g. the cyclooxygenase inhibitor indomethacin (5 mg/kg) in trachea (78%) and seminal vesicle (64%), the serotonin and H1 antagonists cyproheptadine (2 mg/kg) in trachea (88%) and stomach (56%) and the dual cyclooxygenase/lipoxygenase inhibitor phenidone (10 mg/kg) in seminal vesicle (87%). PAF antagonists lexipafant and UR-12460 (10 mg/kg), but not apafant, potently inhibited extravasation in trachea (59, 84%) and seminal vesicle (81, 78%) and in stomach only UR-12460 (52%), whereas all of them were ineffective in thymus. When extravasation was induced by PAF (4 micrograms/kg) a low dose (0.1 mg/kg) of the three PAF antagonists strongly reduced extravasation in thymus and seminal vesicle, whereas lexipafant and UR-12460 did so in trachea (82, 100%) and only lexipafant in stomach (100%). Mepyramine, cyproheptadine, HOE-140 and indomethacin did not inhibit the effect of PAF, whereas phenidone inhibited it by 58% in trachea. These results suggest that most of the LPS-induced increase in vascular permeability is mediated by secondary vasoactive mediators among which PAF plays a pivotal role, although their relative contribution may vary from tissue to tissue.

Animals↗

PubMed1997

[Contribution to the study of dermatomycosis in Catalonia].

We report the results of a study which aim was the mycological identification of specimens coming from patients included in a clinical trial. A total of 445 specimens from patients with clinical diagnosis of dermatomicosis were processed during 8 months (138 pityriasis versicolor, 28 cutaneous candidosis and 279 dermatophytosis). A 48% of pityriasis versicolor cultures were positive for Malassezia furfur, 50% of candidosis cultures were positive for yeasts and 67% of dermatophytosis cultures were positive for dermatophytes. According to our results Candida albicans was the principal causative agent for cutaneous candidosis and Trichophyton mentagrophytes and Trichophyton rubrum were the most frequent isolated species causing dermatophytosis.

English Abstract↗

PubMed1997

Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF).

Rupatadine (UR-12592, 8-chloro-6, 11-dihydro-11-[1-[(5-methyl3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridine ) is a novel compound that inhibits both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with specific receptors (Ki(app) values against [3H]WEB-2086 binding to rabbit platelet membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 microM, respectively). Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 = 9.29 +/- 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4 (LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit platelets (WRP) (pA2 = 6.68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 microM), while not affecting ADP- or arachidonic acid-induced platelet aggregation. Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 micrograms/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine's duration of action was long, as assessed by the histamine- and PAF-induced increase in vascular permeability test in dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects. Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadine's PAF antagonist effects were near those of WEB-2066. Rupatadine is therefore a good candidate for further development in the treatment of allergic and inflammatory conditions in which both PAF and histamine are implicated.

Administration, Oral↗

PubMed1997

Influence of formulation on the in vitro transdermal penetration of flutrimazole.

Flutrimazole (1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1 H-imidazole, CAS 119006-77-8, UR-4056) is a new wide spectrum local imidazolic antifungal agent that has already been formulated as a dermal cream (FDC). A comparative study was carried out of the release of flutrimazole from two emulsions in which the drug has been incorporated differently: one dissolved in the oily phase (E24) and the other dispersed in the aqueous formulation phase (E25). Based on the E25 formulation, two more dermal creams were prepared, E27 with benzyl alcohol and E28 with diazolidinyl urea as preservative agents. A comparative study of transdermal penetration including E27, E28, FDC (reference 1% flutrimazole dermal cream) and 1% flutrimazole hydroalcoholic solution was also performed. An amount of the sample dosage form containing 10 mg of flutrimazole was applied to a Franz type cell. The penetration membrane used was cellulose acetate in the release studies and human skin provided by a plastic surgery clinic in the transdermal penetration study. The amount released after 7 h was 36.3 +/- 4.9 micrograms when flutrimazole was dissolved (E24) and 35.9 +/- 5.3 micrograms when flutrimazole was dispersed (E25). Although the differences were not significant, the cream with dispersed flutrimazole was selected for further penetration studies due to its better stability observed in previous studies. The amounts of drug penetrated after 44 h were 31.3, 41.5, 38.3 and 186.5 micrograms for E27, E28, FDC dermal creams and topical hydroalcoholic solution, respectively. The solution showed a statistically significant difference (p < 0.05) from the other formulations, however, no differences were observed between the dermal cream formulations. No differences were neither obtained between the different dermal creams when the amount of drug retained in the skin was compared. This allows to assert that the excipients used do not have different influences on transdermal penetration. In all cases, the mean quantity penetrated in relation to the dose applied was at most 0.5%. These results allow to infer that flutrimazole shows scarce transdermal penetration. Further, the amount of flutrimazole retained per gram of skin is more than 100 times the MIC per gram obtained in previous in vitro studies. It may be assumed that the topical application of the new formulations assayed would allow to obtain a good therapeutic response.

Administration, Cutaneous↗

PubMed1997

Effects of a new platelet-activating factor antagonist, UR-12670, on several endotoxic shock markers in rats.

UR-12670 is a novel and potent PAF antagonist, eg., it displaces [3H]WEB-2086 from PAF receptors in rabbit platelet membranes (Ki = 0.6 nM) and inhibits PAF-induced increase in vascular permeability in rat trachea (100%), thymus (44%), seminal vesicles (100%) and stomach (54%) at a dose of 0.01 mg/kg i.v. Since PAF is thought to be an important mediator in endotoxic shock, the effect of pretreatment with UR-12670 on changes in vascular permeability, disseminated intravascular coagulation (DIC) and plasma biochemical parameters were determined in a rat model of acute endotoxemia. UR-12670 and the reference PAF antagonist, lexipafant (10 mg/kg i.v.), strongly inhibited lipopolysaccharide (LPS, 25 mg/kg i.v.)-induced plasma leakage in the trachea (49 and 100%, respectively) and seminal vesicles (81 and 100%), as assessed by the Evans blue extravasation method. Only lexipafant inhibited the increase in vascular permeability in the thymus (36%). Neither PAF antagonist was effective in the stomach. Both UR-12670 and lexipafant at 10 mg/kg i.v. attenuated the LPS-induced variation of some DIC markers, such as activated partial thromboplastin time increase (56 and 58%, respectively) and the fibrinogen concentration decrease (53 and 31%), whereas the increase in prothrombin time was not affected. Increased plasma acid phosphatase (ACP, a lysosomal activation marker) and lactate dehydrogenase (LDH, a tissue damage marker) activity elicited by LPS was attenuated by pretreatment with 10 mg/kg i.v. of either UR-12670 or lexipafant (ACP: 55 and 48%; LDH: 50 and 33%). LPS-induced hyperglycemia (46 and 37%) and hyperlactacidemia (100% both) were also inhibited. UR-12670 protected against several shock symptoms, confirming the role of PAF in the pathogenesis of rodent endotoxemia.

Acid Phosphatase↗

PubMed1996

In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280.

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.

Angiotensin II↗

PubMed1996

Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

Administration, Oral↗

PubMed1996

Design, synthesis, and structure-activity relationship studies of novel 1-[(1-acyl-4-piperidyl)methyl]-1H-2- methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor antagonists.

Replacement of the polar head of our previous series of 1-acyl-4-[(2-methyl-3-pyridyl)-cyanomethyl]piperazines with a 2-methylimidazo[4,5-c]pyridine group has led to the identification of a new series of 1-[(1-acyl-4- piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor (PAF) antagonists. On the basis of the general structure--activity relationship trends found for the acyl substituent in our earlier series, five groups of compounds were tested, diaryl- or alkylarylpropanoyl derivatives, their 3-hydroxy-substituted analogues, and urea, carbamate and amino acid derivatives. The optimal compound 19 UR-12670), bearing the 3,3-diphenylpropanoyl moiety, exhibited very high in vitro and in vivo potency IC50 = 0.0076 microM for the in vitro PAF-induced platelet aggregation assay, ID50 = 0.0086 mg/kg for the in vivo PAF-induced hypotension test in normotensive rats, and ID50 = 0.092 mg/kg po and 0.0008 mg/kg i.v. for the PAF-induced mortality test in mice). Compound 19 also showed long duration of activity. It gave 100% protection against PAF-induced mortality in mice 7 h after i.v. administration of a single dose of 1 mg/kg and also provided 100% inhibition of PAF-induced aggregation in dog whole blood 6 h after i.v. administration of the same dose. The lead structure 19 has been selected for in-depth pharmacological evaluation.

Animals↗

PubMed1996

Topical anti-inflammatory properties of flutrimazole, a new imidazole antifungal agent.

The topical anti-inflammatory properties of flutrimazole, a new imidazole antifungal, have been evaluated. Flutrimazole inhibited mouse ear oedema induced by arachidonic acid, tetradecanoylphorbol-acetate and dithranol, with IC50 values of 3.32, 0.55 and 2.42 mumols/ear, respectively. Ketoconazole showed similar potency in arachidonic acid and dithranol models (IC50 = 3.76 and 2.41 mumols/ear) whereas it was less active against tetradecanoylphorbol acetate (IC50 = 1.96 mumols/ear). The standard anti-inflammatory sodium diclofenac was overall slightly more potent than antifungals (IC50 = 2.23, 0.57 and 0.57 mumols/ear against arachidonic acid, tetradecanoylphorbol acetate and dithranol, respectively). Both 2% flutrimazole and 2% ketoconazole creams, applied topically, inhibited carrageenan-induced rat paw oedema by about 40%. Under the same conditions, 1% flutrimazole and diclofenac creams inhibited by 26 and 54%, respectively. Flutrimazole may work through the inhibition of 5-lipoxygenase, as it inhibited LTB4 production by human granulocytes with an IC50 value of 11 microM (IC50 value for ketoconazole was 17 microM), whereas ram seminal vesicle cyclooxygenase was only inhibited by 16% at a concentration of 25 microM. Drugs such as flutrimazole, with dual anti-inflammatory/antifungal activity, may be advantageous in the treatment of topical fungal infections with an inflammatory component.

Administration, Topical↗