Enrico Abignente

Research on heterocyclic compounds, XLI. 2-Phenylimidazo[1,2-b]pyridazine-3-acetic derivatives: synthesis and anti-inflammatory activity

Abstract The synthesis of a group of 2-phenylimidazo[1,2-b]pyridazine-3-acetic esters and acids is described. The structures of the new compounds are supported by 1 H-NMR spectra. These compounds were tested in vivo for their anti-inflammatory, analgesic and ulcerogenic activity. All new compounds showed remarkable anti-inflammatory action in the carrageenan rat paw oedema (one third of that for indomethacin) but no significant analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action, and were also found to be lacking inhibitory activity on cyclooxygenase in vitro.

Research on heterocyclic compounds. XXXVII. Synthesis and antiinflammatory activity of methyl-substituted imidazo[1,2-a]pyrazine derivatives

Summary A series of methyl-substituted imidazo[1,2- a ]pyrazines 8 bearing a carboxylic acid group on the imidazole ring were synthesized. The structures of new compounds were confirmed by 1 H- and 13 C-NMR spectral data; the correct assignment of carbon resonances was made by means of HETCOR and COLOC experiments. Antiinflammatory, analgesic and ulcerogenic activities in vivo were evaluated and compared with those of antiinflammatory imidazopyrazines ( 2 and 3 ) and indomethacin. The inhibitory action on cyclooxygenase activity was evaluated in vitro. Compounds 8 were found to be less potent than indomethacin in these assays. SARs are discussed.

Research on heterocyclic compounds. XXXII. Synthesis and cyclooxygenase-independent antiinflammatory and analgesic activity of imidazo[1,2-a]pyrimidine derivatives

Abstract The synthesis of a group of imidazo[1,2-a]pyrimidine-2-carboxylic esters, acids and amides is described. The structures of the new compounds are supported by 1H- and 13C-NMR spectra. These compounds were tested in vivo for their antiinflammatory and analgesic activities as well as for their ulcerogenic action. The ester 5b, the acid 6c and the amide 7a showed antiinflammatory action in the rat paw edema ( ∼1 3 x indomethacin ), while almost all compounds displayed significant analgesic activity in the acetic acid writhing test, particularly the 5-chloro-7-methyl derivatives 5a, 6a and 7a ( ∼1 5 x indomethacin ). All new compounds were found to be lacking in inhibitory activity on cyclooxygenase in vitro.

Research on heterocyclic compounds — Part XXXIX. 2-Methylimidazo[1,2-a]pyrimidine-3-carboxylic derivatives: Synthesis and antiinflammatory activity

Abstract The synthesis of a group of 2-methylimidazo[1,2- a ]pyrimidine-3-carboxylic esters, acids and amides is described. The structures of new compounds are supported by 1 H and 13 C NMR spectra. These compounds were tested in vivo for their antiinflammatory, analgesic and ulcerogenic activity. Eight new compounds out of fifteenshowed remarkable dose-dependent antiinflammatory action in the carrageenan rat paw edema (1/2–1/3 × indomethacin) but weak analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action. The new compounds were found to be lacking in inhibitory activity on cyclooxygenase in vitro.

T-type channel blocking properties and antiabsence activity of two imidazo (1,2-b)pyridazine derivatives structurally related to indomethacin

It is presently unclear whether the antiseizure effects exerted by NSAIDs are totally dependent on COX inhibition or not. To clarify this point we investigated whether 7-methyl-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM2), two imidazo[1,2-b]pyridazines structurally related to indomethacin (IDM) but ineffective in blocking COXs, retain IDM antiabsence activity. When administered by intraperitoneal injection in WAG/Rij rats, a rat strain which spontaneously develops SWDs, both DM1 and DM2 dose-dependently suppressed the occurrence of these seizures. Importantly, these compounds were both more potent in suppressing SWD occurrence than IDM. As T-type channel blockade is considered a mechanism of action common to many antiabsence drugs we explored by whole cell patch clamp electrophysiology in stably transfected HEK-293 the effect of DM1 and DM2 on Ca(V)3.1 channels, the T-type channel subtype preferentially expressed in ventrobasal thalamic nuclei. Both these compounds dose-dependently suppressed the currents elicited by membrane depolarization in these cells. A similar T-type blocking effect was also observed when the cells were exposed to IDM. In conclusion, DM1 and DM2 whilst inactive on COXs, are potent antiabsence drugs. This suggests that compounds with structural features typical of NSAIDs may exert antiepileptic activity independently from COX inhibition and possibly by a direct interaction with T-type voltage-dependent Ca(2+) channels.

2‐Phenylimidazo[1,2‐a]pyridine‐3‐carboxylic Acid Derivatives: Synthesis and Antiinflammatory Activity

A series of 2‐phenylimidazo[1,2‐a]pyridine‐3‐carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro‐intestinal tract. The most active member of this series of compounds was found to be 6‐methyl‐2‐phenylimidazo[1,2‐a]pyridine‐3‐carboxylic acid (5c).

Galactosyl prodrug of ketorolac: synthesis, stability, and pharmacological and pharmacokinetic evaluations.

Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to D-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.

Galactosylated dopamine enters into the brain, blocks the mesocorticolimbic system and modulates activity and scanning time in Naples high excitability rats

Pathological conditions, such as Parkinsons disease and attention deficit hyperactivity disorder, have been linked to alterations of specific dopamine (DA) pathways. However, since exogenous DA does not cross the blood-brain barrier, DA levels can be modulated e.g. by DA precursors or DA reuptake blockers. Hereby histochemical, analytical and behavioral evidence shows that a galactosylated form of DA (GAL-DA) carries DA into the brain, thus modulating activity and nonselective attention in rats. To this aim adult male rats of the Naples high-excitability (NHE) and random bred controls (NRB) lines were given a single i.p. injection of GAL-DA (10 or 100 mg/kg). Three hours later the behavior was videotaped and analyzed for horizontal activity, orienting frequency and scanning duration. The dose of 100 mglkg of GAL-DA reduced by 25% the horizontal activity in NHE rats, mainly in the first part of the testing period. No effect was observed on orienting frequency or on scanning duration. However, GAL-DA 100 mg/kg was associated with longer rearing episodes in the second part of the testing period in NHE rats. In parallel experiments histochemistry with a galactose-specific lectin showed 10% increase in galactose residues into the striatum between 0.5 and 3.0 h. To quantify the level of GAL-DA, its metabolite DA-succinate and DA in the prefrontal cortex, neostriatum, and cerebellum, rats were killed 2.0 h after the injection of prodrug. Mass high performance liquid chromatography (HPLC) was used for analysis of GAL-DA and DA succinate whereas electrochemical HPLC for DA. Both HPLC techniques demonstrate that GAL-DA carries and releases DA into the brain. Specifically 100 mg/kg of GAL-DA increased DA level in the striatum in the NHE rats only. Moreover, DA in the mesencephalon (MES) was correlated positively with striatal and prefrontal cortex DA in NHE rats. In contrast DA in the MES was negatively correlated with striatal DA in NRB. GAL-DA disrupted these correlations in both rat lines. Thus, this new DA prodrug may modify DA neurotransmission and might have a potential clinical application.

Research on heterocyclic compounds. XXXI: Synthesis and antiinflammatory activity of 2-arylimidazo[1,2-a]pyrazine-3-carboxylic acids

Abstract The synthesis of a series of 2-phenyl- and 2-(p-chlorophenyl)imidazo[1,2-a]pyrazine-3-carboxylic esters and acids is described. The structures of the new compounds were supported by 1H- and 13C-NMR spectra. These compounds were evaluated in vivo for their antiinflammatory and analgesic activities as well as for their ulcerogenic potential. Acids 8c and 8e were found to be the most potent antiinflammatory agents ( ⋍ 1 8 × indomethacin ), while 8a, 8d and 8f displayed analgesic activity ( ⋍ 1 16 × indomethacin ). The inhibitory activity on cyclooxygenase action was evaluated in vitro and discussed in comparison with results obtained in vivo.

Galactosyl derivative of Nω-nitro-L-arginine: Study of antiproliferative activity on human thyroid follicular carcinoma cells

The methyl ester prodrug of Nω‐nitro‐L‐arginine (L‐NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L‐NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of Nω‐nitro‐L‐arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82‐W‐1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L‐NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L‐NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS‐II expression by NAGAL. Finally, by using the LC–MS technique, we found that NAGAL elicited a higher increase in Nω‐nitro‐L‐arginine (NA) concentration than did L‐NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma. J. Cell. Physiol. 221: 440–447, 2009.