Propionic Acid Derivatives Research Articles

Nitrogen-containing compounds from the moss Fontinalis squamosa

The alkaloid harmol and its hitherto unknown propionic acid derivative as well as a new amino acid derivative fontinalin were isolated from the watermoss Fontinalis squamosa. The structures have been elucidated spectroscopically and by independent chemical synthesis.

Stereoselective Biotransformation of the Selective Serotonin Reuptake Inhibitor Citalopram and Its Demethylated Metabolites by Monoamine Oxidases in Human Liver

Citalopram (CIT) is an antidepressive drug of the group of selective serotonin reuptake inhibitors (SSRIs). The tertiary amine CIT is given as a racemic drug, but its pharmacological activity resides mainly in S-CIT. CIT is metabolised by cytochrome P450 (CYP) to N-demethylcitalopram (DCIT) and N-didemethylcitalopram (DDCIT). The citalopram propionic acid derivative (CIT-PROP) is another, but pharmacologically inactive, metabolite, the formation of which has been poorly characterised but is postulated to occur by deamination of CIT, DCIT and/or DDCIT. The aim of the present investigation was to study the formation of the enantiomers of CIT-PROP from CIT and its two N-demethylated metabolites, DCIT and DDCIT, in an in vitro incubation system (microsomal and cytosolic fractions) obtained from human livers. The production of CIT-PROP was measured by a stereospecific HPLC method. Incubation of rac-CIT, rac-DCIT and rac-DDCIT (500 μM each, separately) in the presence (or absence) of NADP showed that CIT-PROP formation was substrate-dependent and essentially NADP-independent. Monoamine oxidases (MAO) type A and B and aldehyde oxidase were identified as the probable enzymes involved in the formation of CIT-PROP from CIT, DCIT and DDCIT. Indeed, the irreversible monoamine oxidase type A inhibitor clorgyline and the irreversible monoamine oxidase type B inhibitor selegiline (both at 0.5 μM in the incubation mixture) inhibited CIT-PROP formation, depending on the substrate, up to 70% and 88%, respectively. The participation of aldehyde oxidase in the subsequent step is suggested by the inhibition caused by menadione (50 μM) in CIT-PROP formation. Preliminary experiments suggest the presence of four unknown metabolites, probably products of deamination, which were detected in plasma and urine samples of patients treated with CIT as well as in in vitro biotransformations. Their presence confirms the importance of deamination in the biotransformation of CIT and its demethylated metabolites, especially in the brain where, in contrast to the liver, the role of cytochrome P450 appears to be low.

Dendrimer-like Star Polymers

Dendrimer-like star polymers, a novel type of molecular architecture, have been synthesized. The architecture of the new polymers resembles that of three-dimensional spherical dendrimers as well as classical star polymers. The controlled structures, based on aliphatic polyesters, are synthesized by a divergent growth approach. A hexa hydroxy-functional 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) derivative was used as the “initiator” for the stannous-2-ethylhexanoate (Sn(Oct)2) catalyzed living ring opening polymerization of e-caprolactone. The polymerization generated a six-arm polymer with a molecular weight of 14 300 (Mn) and a Mw/Mn of 1.06. The new polymer was functionalized with a protected bis-MPA, deprotected, and used as the “macroinitiator” for the polymerization of a second generation 12 armed poly(e-caprolactone) (Mn = 42 300, Mw/Mn = 1.16). Another iteration of the same procedure generated a third generation 24 arm dendrimer-like star polymer with a Mn of 96 000 and Mw/Mn of 1.14. The comp...

Effect of Chemical Structure on the Release of Certain Propionic Acid Derivatives from Their Dosage Forms

The aim of this study was to investigate the relationship between the chemical structure and release properties of certain drug products. Propionic acid derivatives were used as a model. These include ibuprofen (I), ketoprofen (K), tiaprofenic acid (T), flurbiprofen (F), and naproxen (N). They are all aryl derivatives of propionic acid and differ only in the aryl group. Such an aryl group may be either isobutylphenyl, benzoylphenyl, benzoylthienyl, fluorobiphenyl, or methoxynaphthyl group in I, K, T, F, and N, respectively. Three dosage forms were selected for this study: capsules, suppositories, and creams. The release of propionic acid derivatives from the capsules and suppositories decreased in the order ibuprofen tiaprofenic acid > ketoprofen > flurbiprofen > naproxen, and for the creams the release decreased in the order ibuprofen > tiaprofenic acid > flurbiprofen > ketoprofen > naproxen. The difference in drug release in the first case was attributed to the difference in the chain length, and in the creams which are composed of two phases, the partition coefficient was found to affect the drug release. The molecular weight of the drug had no effect on the release. The drug release from different dosage forms was not affected after 1 month storage.

When are NSAIDs appropriate in osteoarthritis?

Osteoarthritis is a multifactorial disease that is more common in the elderly than in younger individuals. Opinion is divided on whether it is a degenerative or inflammatory process. Most rheumatologists accept that the disease has an inflammatory component, particularly when it is complicated by crystal deposition. Nonsteroidal anti-inflammatory drugs (NSAIDs) are particularly toxic in the elderly. The geriatrician should use a more conservative approach to initial therapy, which should include patient education, physiotherapy and even the consideration of intra-articular steroid injections. If systemic drug therapy is still required, simple analgesics should usually be tried first. If NSAIDs are then required, they can be selected according to their chemical structure (which bears some relation to adverse effects) or half-life (which is more relevant to optimum prescribing). Propionic acid derivatives are well established and remain the NSAIDs of choice: agents with a short half-life, perhaps given in low dosages, are preferred. The use of topical formulations, which are more expensive, may avoid some adverse effects; however, drug effects are unlikely to remain truly localised. It may be prudent to provide gastroprotective therapy for some elderly patients. A full evaluation of the new generation of cyclooxygenase-2 inhibitors in osteoarthritis is still awaited.

Quantitative structure-activity relationship analysis of a series of trans-octahydro-11-oxodibenzo-[ b,e]-thiepin propionic acid derivatives

The structures of a series of antiinflammatory trans-octahydro-11-oxodibenzo-[ b,e]-thiepin propionic acid ester and amide derivatives were submitted to molecular modeling software, and after energy minimization of the structures, a number of electronic, spatial and thermodynamic descriptors were calculated. After quantitative structure-activity relationship (QSAR) analysis the result showed that the electronic descriptors, especially partial atomic charges on C15 and C18, have important effects on the oral anti-inflammatory activity.

Cystitis and interstitial nephritis related to the use of tiaprofenic acid (Surgam™)

We describe a case of concurrent presentation of severe haemorrhagic cystitis and acute interstitial nephritis with eventually lethal outcome, associated with the use of tiaprofenic acid (Surgam™), a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID). Although interstitial nephritis and haemorrhagic cystitis are caused by all types of NSAIDs, a higher incidence of interstitial nephritis and especially haemorrhagic cystitis has been described related to propionic acid derivatives. Awareness of this serious adverse effect is important.

Synthesis of a Series of Potent and Orally Bioavailable Thrombin Inhibitors That Utilize 3,3-Disubstituted Propionic Acid Derivatives in the P3 Position

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

ChemInform Abstract: Structure and Properties of New Ligands on the Base of Propionic Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Comparative mutagenic and genotoxic effects of three propionic acid derivatives ibuprofen, ketoprofen and naproxen

The mutagenicity of three propionic acid derivatives, namely ibuprofen, ketoprofen and naproxen, was tested in the Ames mutagenicity assay (in strains TA97a, TA100 and TA102) and in vivo genotoxicity was tested by sister chromatid exchange (SCE) in bone marrow cells of mice. These are the anti-inflammatory drugs frequently used in different parts of the world. Mutagenicity results showed no mutagenic effects in strains TA97a, TA100 and TA102 for all three drugs. Results of in vivo SCE assays indicate that these three drugs are weakly genoxic in bone marrow cells of mice. This is the first report of the Ames mutagenicity assay for ketoprofen and in vivo SCE assay for three drugs.

3-Substituted-4-hydroxy-7-chromanylacetic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor

The SAR of a series of 7-chromanylacetic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists. We found optimal activity in derivatives with c~,c~-disubstitution on the acetic acid and a C-4 hydroxy group and a C-3 lipophilic group on the chromane ring. CP-105696 (43), which contains a 4-phenylbenzyl C-3 substituent, was selected for development. ~ 1997 Elsevier Science lad. LTB4 is a potent chemoattractant for granulocytes (e.g., neutrophils and eosinophils) and stimulates functional responses such as secretion and cytokine synthesis in these cells as well as in mononuclear cells and lymphocytes. Its presence in relevant tissues has implicated it to be a likely mediator in a number of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma. Receptor antagonists of LTB4 are thus expected to be useful therapeutics tbr these diseases. To date, compounds from several structural classes have been discovered to display LTB4 antagonismJ During the course of our investigations on leukotriene D4 antagonists, we observed that certain chromanol derivatives displayed modest LTB4 antagonism in addition to LTD4 antagonism. We also noted that of all the NSAIDs examined, only the propionic acid class showed any significant parallel between their ability to block (3H) LTB4 binding to high affinity receptors on guinea pig spleen membranes and their ability to inhibit LTB4-induced human neutrophil chemotaxis} These observations led us to prepare hybrid molecules with the aim of identifying potent and selective LTB4 antagonists. Accordingly, the propionic acid derivatives 1

Bacillus stearothermophilus as a model to evaluate membrane toxicity of a lipophilic environmental pollutant (DDT).

The thermophilic eubacterium Bacillus stearothermophilus has been used as a model system to identify DDT-promoted events in biological membranes putatively related with the insecticide toxicity. Two strategies have been approached: a) bacterial growth and viability were followed and the effects of DDT (2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane) determined; b) biophysical studies with fluorescent probes were performed to elucidate the effects of DDT on the organization of the membrane lipid bilayer. The effects of DDT on growth and physical properties of the membrane were also determined in the presence of Ca2+ to further identify the interference of the insecticide at the membrane level and its putative contribution to cell toxicity. Growth inhibition by DDT is concentration-dependent, being attenuated or removed by the addition of 2.5-mM Ca2+ to bacterial cultures. Consistently, fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and its propionic acid derivative (DPH-PA) exhibited opposite effects of Ca2+ and DDT on the physical state of bacterial polar lipid dispersions. Growth and viability of bacterial cells are affected by DDT concentrations lower than those able to induce detectable bulk fluidity alterations, indicating high sensitivity of the intact bacterial system to alterations in limited membrane domains not directly probed by fluorescent probes that only report the average behavior of membrane lipid population.

Effect of Fenitrothion on Hepatopancreas Microsomal Membrane Fluidity inMacrobrachium borellii

The effects of the organophosphorus insecticide fenitrothion [phosphorothioic acid,O,O-dimethylO-(3-methyl-4-nitrophenyl) ester] on the physical state of microsomal membranes from the hepatopancreas of the freshwater shrimpMacrobrachium borelliiwere investigated. Physical properties of native membranes and liposomes obtained from their total lipids were studied by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), probing the bilayer core, and by its anionic propionic acid derivative (DPH–PA), probing the outer regions of the bilayer. Fenitrothion was found to increase DPH and DPH–PA polarization of microsomal and liposomal membranes when addedin vitroat concentrations within the order of 10−6M. No significant effects were observed in membranes from animals exposed to the insecticidein vivo.Nevertheless, the effect of fenitrothion on the microsomes of exposed animals is observed in a lesser degree than on those from control animals, suggesting an adaptation of the membranes to fenitrothion. Considering that this effect is lower in the liposomes of control and exposed animals, the adaptation seems to involve the protein moiety of the membranes. Fluorescence anisotropy lifetimes (determined by phase-shift (>P) and demodulation (>M) techniques) of DPH were decreased by 0.72 μM fenitrothion in microsomes. The limiting anisotropy of DPH is increased in native membranes that contain fenitrothion, indicating a further ordering effect.

A Facile Synthesis of (4S)-4-[(1R)-1-Carboxyethyl]-1-(tert-butyldimenthylsilyl)azetidin-2-one: A Key Intermediate of 1-β-Methylcarbapenems

Titanium enolate-mediated aldol-type reaction of the chiral N-propionyl-1,3-benzoxyzinone 4 with 4-acetoxyazetidin-2-one (5) gave the 2-(2-oxoazetidin-4-yl)propionic acid derivative 6 in high yield with high selectivity, which was transformed into (4S)-4-[(1R)-1-carboxyethyl]-1-(tert-butyldimethylsilyl)azetidin-2-one (3), a key intermediate of 1-β-methylcarbapenems 1.

Anti-inflammatory, analgesic and ulcerogenic properties of S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin.

The anti-inflammatory, analgesic and gastric mucosal damage-inducing activities of S-(+)-ibuproxam, and S-(+)-ibuproxam-beta-cyclodextrin, new propionic acid derivatives, and racemic ibuproxam-beta-cyclodextrin were investigated in three animal models and compared with those of racemic ibuproxam, racemic ibuprofen and its optical enantiomer S-(+)-ibuprofen. The anti-inflammatory activities of racemic ibuprofen, S-(+)-ibuprofen and racemic ibuproxam in carrageenan-induced paw oedema in rats were almost equipotent and slightly greater than those of S-(+)-ibuproxam and S-(+)-ibuproxam-beta-cyclodextrin, and significantly greater than that of racemic ibuproxam-beta-cyclodextrin. In abdominal constriction tests in mice, the analgesic effects of racemic ibuproxam, S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin were significantly less pronounced than those of racemic ibuprofen and S-(+)-ibuprofen. Ulcerogenic activity of S-(+)-ibuproxam-beta-cyclodextrin in rats was found to be significantly weaker than that of racemic ibuproxam-beta-cyclodextrin, racemic ibuproxam and S-(+)-ibuproxam and, most notably, weaker than those of racemic ibuprofen and S-(+)ibuprofen. These results indicate that S-(+)-ibuproxam-beta-cyclodextrin could be a novel potent anti-inflammatory and analgesic agent with a therapeutic index more favourable than that of the classical non-steroid anti-inflammatory drugs ibuprofen and ibuproxam.

Fatty acid modification of membrane fluidity in Chinese hamster ovary (TR715-19) cells

Dietary saturated fatty acids, especially lauric (12:0), myristic (14:0) and palmitic (16:0) acids, which are hypercholesterolemic, influence cell membrane fatty acid composition and affect LDL receptor function. When membrane phospholipid fatty acids in Chinese hamster ovary cells, containing the human LDL receptor, were modified (Hannah J. S. et al., 1995 Metabolism 44, 1428–1434), LDL receptor function was affected, but correlations with DPH-determined membrane fluidity were weak. The role of fluidity in various membrane domains with respect to the LDL receptor is examined here. Membrane fluidity was assessed by measuring steady-state fluorescence polarization of diphenylhexatriene (DPH) and its polar propionic acid (DPH-PA) and trimethylammonium (TMA-DPH) derivatives from 38 to 4°C in fatty acid modified Chinese hamster ovary cells. Fatty acid changes modulated mid-bilayer fluidity as determined with DPH, but fluidity in phospholipid headgroup domains, assessed with DPH-PA and TMA-DPH, was independent of fatty acyl composition. The DPH fluidity was related to membrane unsaturation ( P < 0.02), oleate contents ( P < 0.009) in particular, but inversely related ( P < 0.0002) to the longer chain (≥ 20 C atoms) unsaturated fatty acids with from four to six double bonds. The LDL binding was independent of fluidity, but there were weak relations between LDL internalization and DPH-PA anisotropy and between LDL degradation and TMA-DPH anisotropy. It was concluded that LDL binding was not related to mid-bilayer fluidity, but the results with the polar probes suggest a role of fluidity in modulating vertical displacement of the LDL/LDL receptor complex across the plasma membrane.

Combined flurbiprofen and cyclosporin-A does not attenuate bone loss and exaggerates renal impairment

Cyclosporine (CsA) is a potent immunosuppressant that has revolutionized the success of organ transplantation. Flurbiprofen (FB), a propionic acid derivative NSAID, has been demonstrated in vivo to reduce osteoclast numbers in normal rats. The aim of this experiment was to determine whether addition of FB to CsA-treated rats could prevent the bone changes associated with CsA therapy. Forty-eight 10–12-week-old male Sprague-Dawley rats were randomized to receive, daily for 28 days: (1) CsA vehicle p.o. plus FB vehicle sc; (2) CsA (15 mg/kg) p.o. plus FB vehicle sc, (3) CsA vehicle p.o. plus FB (1.5 mg/kg) sc; and (4) CsA (15 mg/kg) p.o. plus FB (1.5 mg/kg) sc. Rats were weighed and venous blood sampled at baseline, 14 days, and 28 days for determination of glucose, Ca ++, BUN, creatinine, PTH, osteocalcin, and 1,25(OH) 2 vitamin D. Tibiae were removed following killing, after double labeling for histomorphometry. Body mass was significantly lower than control in all rats receiving CsA on days 14 and 28 while blood glucose was only elevated in the CsA alone group. Day 28 BUN and creatinine were significantly elevated in the CsA group and the combination of CsA and FB revealed an exacerbation of this trend. Vitamin D and osteocalcin were consistently increased in the CsA and CsA/FB groups. Bone histomorphometry showed evidence of trabecular osteopenia in CsA and CsA/FB groups. CsA alone resulted in elevated bone turnover. FB was unable to prevent the trabecular bone loss induced by CsA therapy. This experiment indicates no role for FB as a therapeutic option in CsA-induced bone disease at the given doses and duration of treatment by virtue of its lack of bone sparing ability and adverse renal effects when the two drugs are administered concurrently.

Use of Bacillus stearothermophilus as a model to study tamoxifen-membrane interactions

A strain of Bacillus stearothermophilus was used as a model to study the interaction of tamoxifen (TAM) with the cell membrane and the cytostatic antiproliferative effects not related to oestrogen binding. The bacterial growth in the presence of TAM was evaluated turbidimetrically and by viable cell counting. In parallel, partition coefficients of TAM in bacterial polar lipid bilayers were determined. Additionally, studies with fluorescent probes were carried out to investigate TAM effects on the physical state of the membrane lipid bilayer. TAM inhibits growth of B. stearothermophilus and induces loss of cell viability as a function of concentration and the growth temperature. High partitioning of this drug in the bacterial lipid membranes was observed, reaching maximal values in the temperature range of the phase transition. Fluorescence polarizations of 1,6-diphenyl-1,3,5-hexatriene (DPH) and of its propionic acid derivative (DPH-PA) report significant structural disorder of the lipid bilayer induced by the cytostatic, particularly in the phase transition range. A putative relationship between growth impairment by TAM and the TAM-induced perturbation of the physical behaviour of bacterial membrane lipids is suggested.

Interaction of ethylazinphos with the physical organization of model and native membranes

The interaction of ethylazinphos with the physical organization of model and native membranes was investigated by means of fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and of its propionic acid derivative (DPH-PA). Ethylazinphos shifts the phase transition midpoint to lower temperature values and broadens the phase transition profile of bilayers reconstituted with dimyristoyl-, dipalmitoyl- and distearoylphosphatidylcholines (DMPC, DPPC, DSPC), as detected by DPH and DPH-PA. Additionally, both probes detect significant effects of ethylazinphos in the fluid phase of the above lipid bilayers. The insecticide perturbations are more pronounced in bilayers of short-chain lipids, e.g., DMPC, in correlation with the higher partition in these membranes. On the other hand, the insecticide increases to some extent the ordering promoted by cholesterol in the fluid phase of DMPC, but high cholesterol concentrations (≥ 30 mol%) almost prevent insecticide interaction, as revealed by DPH and DPH-PA. In agreement with the results in models of synthetic lipids, the increase of intrinsic cholesterol in fluid native membranes depresses the partition values of ethylazinphos and consequently its effects.

The Analgesic Interaction of Misoprostol with Nonsteroidal Anti-Inflammatory Drugs.

The purpose of this project was to evaluate the analgesic efficacy of misoprostol when combined with ibuprofen or diclofenac Na. Animal experiments using the inflamed rat paw formalin model suggested that misoprostol potentiates the analgesic effect of some NSAIDs (nonsteroidal anti-inflammatory drugs) including diclofenac Na but not propionic acid derivatives or opiates. The dental pain model was used to evaluate the clinical relevance of this interaction. Patients received a single oral dose of study medication following surgical removal of impacted teeth. Patients were medicated for moderate to severe postsurgical pain and then filled in an analgesic diary for a 6-h observation period. Several blood samples were taken over the observation period. In addition, microdialysis samples were taken directly from the extraction socket and were analyzed for immunoreactive prostaglandin E(2) levels. The studies were single-dose, parallel group and double-blind assays. In the first study, 70 patients received an oral dose of either placebo (n = 13), misoprostol 200 &mgr;g (n = 18), ibuprofen 200 mg (n = 19), or the combination of misoprostol + ibuprofen (n = 20). Misoprostol alone demonstrated a small analgesic effect compared to placebo. Both the ibuprofen and combination groups were substantially more effective than placebo but not different from each other. The combination group had higher ibuprofen blood levels during the first 45 min but had a lower C(max) and longer time to T(max). The second study evaluated oral doses of placebo (n = 11), misoprostol 200 &mgr;g (n = 21), diclofenac Na 50 mg (n = 18), and the combination of misoprostol + diclofenac Na (n = 20). Relative to placebo, misoprostol performance was similar to the first study. When the results of the two studies were combined, there was a small, but statistically significant, analgesic effect for misoprostol. Diclofenac Na was superior to both placebo and to misoprostol alone. The combination was the most effective treatment, and for hours 4--6 it was significantly better than diclofenac Na alone. Analysis of the blood samples showed an earlier and higher peak effect for the diclofenac Na group compared to the combination, and the combination again had a lower C(max). The microdialysis probe assays demonstrated that misoprostol depressed PGE(2) levels at the peripheral site of trauma over the first 2 h after surgery. These pilot studies used small samples, and the results only suggest trend effects. Both studies demonstrated that misoprostol 200 &mgr;g, a prostaglandin analog, does have an analgesic effect. When combined with ibuprofen, there was no potentiation of analgesia. In contrast, the combination of misoprostol + diclofenac Na demonstrated an enhanced peak effect, total effect for pain intensity difference and pain relief (sum pain intensity difference [SPID] and total pain relief [TOTPAR]), and