High analgesic and anti-inflammatory in vivo activities of six new hybrids NSAIAs tetrahydropyran derivatives

We present in this article syntheses of six new hybrids compounds (4–9) that were efficiently prepared in one or two steps (70–84.6%) from our previous prototype (±)-cis-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methanol (3) and the NSAIAs: acetyl salicylic acid, indomethacin, ibuprofen, ketoprofen, naproxen and diclofenac. The acetic acid-induced writhing method is able to determine that all investigated new hybrids showed stronger antinociceptive properties (2- to 10-fold less ED₅₀ values) than their precursors. The highest antinociceptive effect was observed for compound 9 showing more than 10-fold less ED₅₀ values than diclofenac and ninefold less ED₅₀ value than compound 2. All compounds presented greater activity than the control group in the tail-flick test confirming the central antinociceptive effect. New hybrids did not alter the motor performance of mice by rota-rod performance and open-field tests. Investigated compounds 4–9 were not toxic after oral administration (LD₅₀ >2000 mg/kg).     

Interaction between Heliopsis longipes extract and diclofenac on the thermal hyperalgesia test

Heliopsis longipes is an herbaceous plant found in Mexico, used traditionally for its analgesic and anesthetic activities. Plant extracts in combined use with synthetic drugs may represent a therapeutic advantage for the clinical treatment of pain, allowing the use of lower doses, and limiting side-effects. Therefore, the main objective of this study was to determine the possible pharmacological interaction between Heliopsis longipes ethanolic extract (HLEE) and diclofenac in the Hargreaves model of thermal hyperalgesia in the mouse. HLEE, diclofenac or fixed-dose ratio HLEE–diclofenac combinations were administered systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED₃₀ values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED₃₀ value for the HLEE–diclofenac combination was 54.4±9.4 mg/kg body wt, significantly higher than the actually observed experimental ED₃₀ value, 8.6±4.0 mg/kg body wt. This result corresponds to synergistic interaction between HLEE and diclofenac in the Hargreaves model of thermal hyperalgesia. Data suggest that low doses of the HLEE–diclofenac combination can interact synergistically at the systemic level and that this association may therefore represent a therapeutic advantage for the clinical treatment of inflammatory pain.     

Synthesis,and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED₅₀ = 32.08 mg/kg, MES test) and 9 (ED₅₀ = 40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.     

Synergistic interactions between the antinociceptive effect of Rhodiola rosea extract and B vitamins in the mouse formalin test

AimIn this study, the pharmacological interactions between a Rhodiola rosea ethanol extract and B-vitamins such as thiamine (B₁), riboflavine (B₂), pyridoxine (B₆), cyanocobalamin (B₁₂) and a mixture of vitamins B₁ + B₆ + B₁₂ was investigated in the mouse formalin test.MethodsIndividual dose response curves of the Rhodiola rosea ethanol extract, as well as B-vitamins alone or in a mixture were evaluated in mice in which nociception was induced with 2% formalin intraplantarly. The antinociceptive mechanisms of the Rhodiola rosea were investigated by exploring the role of the opioid and serotonin receptors and the nitric oxide pathway. Isobolographic analysis was used to evaluate the pharmacological interactions between the Rhodiola rosea ethanol extract and each B-vitamin individually or the mixture of vitamins B₁ + B₆ +B₁₂ by using the ED₃₀ and a fixed 1:1 ratio combination.ResultsAdministration of the Rhodiola rosea extract alone or in combination with all of the vitamins produced a significant and dose-dependent antinociceptive response. The antinociceptive effect of the Rhodiola rosea extract (ED₅₀ = 81 mg/kg, p.o.) was significant and reverted in the presence of antagonists of the 5-HT_1A, GABA/BDZs and opioid receptors and by blocking mediators of the nitric oxide/cGMP/K⁺ channels pathway. Isobolograms demonstrate that all of the combinations investigated in this study produced a synergistic interaction experimental ED₃₀ values were significantly smaller than those calculated theoretically.ConclusionsThese results provide evidence that a Rhodiola rosea ethanol extract in combination with B-vitamins produces a significant diminution in the nociceptive response in a synergistic manner, which is controlled by various mechanisms. These findings could aid in the design of clinical studies and suggest that these combinations could be applied for pain therapy.     

Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes

We describe herein the design, synthesis and pharmacological evaluation of novel 3-arylamine-imidazo[1,2-a]pyridine derivatives structurally designed as novel symbiotic prototypes presenting analgesic and anti-inflammatory properties. The derivatives obtained were submitted to in vivo assays of nociception, hyperalgesia and inflammation, and to in vitro assays of human PGHS-2 inhibition. These assays allowed the identification of compound LASSBio-1135 (3a) as an anti-inflammatory and analgesic symbiotic prototype. This compound inhibited moderately the human PGHS-2 enzyme activity (IC₅₀ = 18.5 μM) and reverted the capsaicin-induced thermal hyperalgesia (100 μmol/kg, po) similarly to p38 MAPK inhibitor SB-203580 (2). Additionally, LASSBio-1135 (3a) presented activity similar to celecoxib (1) regarding the reduction of the carrageenan-induced rat paw edema (33% of inhibition at 100 μmol/kg, po). We also discovered derivatives LASSBio-1140 (3c) and LASSBio-1141 (3e) as analgesic and anti-inflammatory prototypes, which were able to attenuate the capsaicin-induced thermal hyperalgesia (100 μmol/kg, po) and reduce the carrageenan-induced paw edema (ED₅₀ = 11.5 μmol/kg (3.3 mg/kg) and 14.5 μmol/kg (4.1 mg/kg), respectively), being both more active than celecoxib (1), despite the fact that their effects involve a different mechanism of action. Additionally, derivative LASSBio-1145 (3j) showed remarkable analgesic (ED₅₀ = 22.7 μmol/kg (8.9 mg/kg)) and anti-inflammatory (ED₅₀ = 8.7 μmol/kg (3.4 mg/kg)) profile in vivo (100 μmol/kg; po), in AcOH-induced abdominal constrictions in mice and carrageenan-induced rat paw edema models, respectively, being a novel orally-active anti-inflammatory drug candidate that acts as a selective PGHS-2 inhibitor (IC₅₀ = 2.8 μM).     

Celecoxib analogs possessing a N-(4-nitrooxybutyl)piperidin-4-yl or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridin-4-yl nitric oxide donor moiety: Synthesis,biological evaluation and nitric oxide release studies

A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a–b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a–b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4–5.8% range). In comparison, the percentage NO released was higher (3.1–8.4% range) when these nitrate prodrugs were incubated in the presence of l-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure–activity relationship data acquired showed that compounds having a MeSO₂ COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H₂NSO₂ substituent. Compounds having a MeSO₂ COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED₅₀ = 132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED₅₀ = 118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED₅₀ = 128.7 mg/kg po) but lower than ibuprofen (ED₅₀ = 67.4 mg/kg po).     

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone

A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED₅₀ value of 47.57 mg/kg in MES (mice, ip, 1 h after administration) and at the same time its TD₅₀ was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD₅₀/ED₅₀) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED₅₀ values in MES test (mice, ip) ranged 80–110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.     

Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test

AimsRecent evidence has shown that systemic administration of sulfonylureas and biguanides block the diclofenac-induced antinociception, but not the effect produced by indomethacin. However, there are no reports about the peripheral interaction between analgesics and the biguanides metformin and phenformin. Therefore, this work was undertaken to determine whether glibenclamide and glipizide and the biguanides metformin and phenformin have any effect on the peripheral antinociception induced by diclofenac and indomethacin.Main methodsDiclofenac and indomethacin were administered locally in the formalin-injured rat paw, and the antinociceptive effect was evaluated using the 1% formalin test. To determine whether peripheral antinociception induced by diclofenac or indomethacin was mediated by either the ATP-sensitive K⁺ channels or biguanides-induced mechanisms, the effect of pretreatment with the appropriates vehicles or glibenclamide, glipizide, metformin and phenformin on the antinociceptive effect induced by local peripheral diclofenac and indomethacin was assessed.Key findingsLocal peripheral injections of diclofenac (50–200 μg/paw) and indomethacin (200–800 μg/paw) produced a dose-dependent antinociception during the second phase of the test. Local pretreatment with glibenclamide, glipizide, metformin and phenformin blocked the diclofenac-induced antinociception. On the other hand, the pretreatment with glibenclamide and glipizide did not prevent the local antinociception produced by indomethacin. Nonetheless, metformin and phenformin reversed the local antinociception induced by indomethacin.SignificanceData suggest that diclofenac could activate the K⁺ channels and biguanides-dependent mechanisms to produce its peripheral antinociceptive effects in the formalin test. Likewise, a biguanides-dependent mechanism could be activated by indomethacin consecutively to generate its peripheral antinociceptive effect.     

Design,synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies

A new series, 2-substituted mercapto-3-[2-(pyridin-2-yl)ethyl]-4(3H)-quinazolinone 1–21, was synthesized and evaluated for in vivo anti-inflammatory and analgesic activities and in vitro COX-1/COX-2 inhibition. Compounds 1, 4, 5, 6, 8, 10, 13, 14, 15, 16, and 17 exhibited potent anti-inflammatory and analgesic properties, with ED₅₀ values of 50.3–112.1 mg/kg and 12.3–111.3 mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED₅₀ = 112.2 and 100.4 mg/kg) and celecoxib (ED₅₀ = 84.3 and 71.6 mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC₅₀ (0.33 μM and 0.40 μM, respectively) and selectivity index (SI > 303.0 and >250.0, respectively) values that are similar to those of the reference drug celecoxib (IC₅₀ 0.30 μM and COX-2 SI > 333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC₅₀ values of 0.70–0.80 μM and COX-2 SI > 125–142. Potent COX-2 inhibitors, such as compounds 4, 6, and 13, were docked into the active site pockets of COX-1 and COX-2, with the greatest recognition occurring at the COX-2 binding site and insignificant interactions at the binding site of the COX-1 pocket.     

New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5–38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED₅₀ MES = 74.8 mg/kg, ED₅₀ scPTZ = 51.6 mg/kg, ED₅₀ 6 Hz = 16.8 mg/kg) which showed TD₅₀ = 213.3 mg/kg in the chimney test that yielded satisfying protective indexes (PI MES = 2.85, PI scPTZ = 4.13, PI 6 Hz = 12.70) at time point of 0.5 h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.     

Seizure prevention by the naturally occurring phenols,carvacrol and thymol in a partial seizure-psychomotor model

The natural compounds carvacrol and thymol completely prevented seizures in the 6 Hz, 32 mA partial seizure model. Carvacrol and thymol, both exhibited an ED₅₀ = 35.8 mg/kg, ip and yielded protective indices of 5.3 and 3.4, respectively. At 44 mA current intensity, carvacrol and thymol exhibited ED₅₀s of 88.82 mg/kg (PI = 2.15) and 73.0 mg/kg (PI = 1.65), respectively. Thymol, but not carvacrol showed partial inhibitory activity in the maximal electroshock (MES), sc Metrazol (scMET) and Corneal-kindled models. These results suggest that carvacrol and thymol are more efficacious anticonvulsants than suggested by their lower efficacies in the conventional MES and scMET tests.     

Molecular design,synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1–4.0 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 8a as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 72.4 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO₂NH₂ group underwent H-bonding interaction with Gln¹⁹²(2.95 Å), Phe⁵¹⁸(2.82 Å) and Arg⁵¹³(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Design and comparative anticonvulsant activity assessment of CNS-active alkyl-carbamoyl imidazole derivatives

A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6 Hz psychomotor (6 Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties.In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED₅₀ values ranging from 12 to 20 mg/kg coupled with high protective index (PI = TD₅₀/ED₅₀) values of 4.1–7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED₅₀ values of 14–26 mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6 Hz model with ED₅₀ values of 32 and 44 mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy–safety profile and consequently, might be promising candidates for development as new antiepileptics.     

Synthesis of 1-(methanesulfonyl- and aminosulfonylphenyl)acetylenes that possess a 2-(N-difluoromethyl-1,2-dihydropyridin-2-one) pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO₂Me or SO₂NH₂ group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO₂Me regioisomers, and the 4-SO₂NH₂ analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC₅₀ = 3.2–3.5 μM range) relative to the reference drug caffeic acid (IC₅₀ = 4.0 μM). The SO₂Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO₂Me, 4-SO₂Me and 4-SO₂NH₂ compounds, with respective ED₅₀ values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED₅₀ = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.     

Design,synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives

Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC₅₀ 1.5–29.9 μM) and galvinoxyl radicals (IC₅₀ 4.9–41.1 μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH = 7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (log P = 3.48), suggesting a potential ability to penetrate the blood–brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7 mg/mL) has also been significantly improved as compared with curcumin (<0.1 mg/mL).     

Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide in the mouse tail-flick and hot-plate tests

The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α₂-adrenergic, and I₂ imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ET_A receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α₂-adrenoceptor antagonist), idazoxan (α₂-adrenoceptor/I₂-imidazoline antagonist), BU224 (I₂-imidazoline antagonist) or BQ123 (endothelin ET_A receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED₅₀ values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α₂-adrenergic, I₂-imidazoline and endothelin ET_A receptors are not involved in 1c antinociception.     

Design,synthesis and anticonvulsant activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides

The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED₅₀ MES = 96.9 mg/kg, ED₅₀ scPTZ = 75.4 mg/kg, ED₅₀ 6 Hz = 44.3 mg/kg) which showed TD₅₀ = 335.8 mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES = 3.5, PI scPTZ = 4.4, PI 6 Hz = 7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.     

Antithrombotic effects of LB30870, a potent,orally active,selective and direct thrombin inhibitor,and pharmacokinetics of its prodrug

Antithrombotic activity and bleeding complication of a new potent, selective, and direct thrombin inhibitor, LB30870, were evaluated in comparison with other anticoagulants. In order to improve oral absorption of LB30870, pharmacokinetics of LB30889, which is a double prodrug with blocking groups in both amidine and carboxyl groups, was studied in rats and dogs. LB30870 was more potent than melagatran or argatroban with thrombin inhibition constants of 0.02, 1.3 and 4.5 nM, respectively. All three direct thrombin inhibitors were selective towards other serine proteases with selectivity ratio greater than 1000, except for trypsin. Thrombin binding kinetics of LB30870 showed rapid association and slow dissociation rate constants, demonstrating its potential as anticoagulant. LB30870 was more effective than melagatran or argatroban in plasma clot-bound thrombin inhibition. In the rat venous stasis model of the caval vein, LB30870 reduced wet clot weights in a dose dependent manner after the intravenous bolus with infusion administration. The ED₅₀ of LB30870, melagatran and enoxaparin were 50 μg/kg + 2 μg/kg/min, 35 μg/kg + 1.4 μg/kg/min and 200 μg/kg + 8.3 μg/kg/min, respectively. No significant bleeding problem was observed with LB30870 at the dose up to two times ED₈₀ in rats. LB30889, a double prodrug of LB30870, showed species difference in pharmacokinetics. Its oral bioavailability in rats or dogs was not better than that of LB30870. In conclusion, LB30870 has the potential to be useful as an effective oral anticoagulant for the prevention and treatment of thromboembolic diseases.     

Search for anticonvulsant and analgesic active derivatives of dihydrofuran-2(3H)-one

A series of derivatives of dihydrofuran-2(3H)-one (γ-butyrolactone, GBL) was synthesized and tested for anticonvulsant, neurotoxic and analgesic activity. In the anticonvulsant screening 10 lactones were effective in the maximal electroshock test (MES) at the highest doses (300 and 100 mg/kg, 0.5 h, ip, mice). Statistical analysis showed correlation between the anticonvulsant activity and relative lipophilicity parameters determined by experimental and computational methods (R_M0, C log P and M log P). Preliminary antinociceptive evaluation of selected derivatives revealed strong analgesic activity. The majority of the tested compounds showed high efficacy in animal models of acute pain (hot plate and writhing tests) and strong local anesthetic activity (modified tail immersion test). The obtained ED₅₀ values were comparable with such analgesics as acetylsalicylic acid and morphine.