New fluorescent derivatives for s receptors were designed and synthesized. To achieve this purpose, a 4-nitro-2,1,3-benzoxadiazole fluorescent tag was connected through a piperazine linker to a modified skeleton derived from selected s receptor agonists or antagonists. Compounds 5g, 7b, 7e and 7g displayed high s1 affinity and low s1/s2 selectivity (Kis1 ranging from 31.6 nM to 48.5 nM, Kis1/s2 ¼ 5–18), while compound 5d exhibited high s2 affinity and selectivity (Kis2 ¼ 56.8 nM, Kis1 > 5000 nM). Binding affinity studies revealed that compounds 5d, 5g, 7b, 7e and 7g showed no affinity towards several receptors including opioid, dopaminergic, serotonergic, adrenergic, muscarinic, histaminergic, N-methyl-D-aspartate (NMDA), NMDA receptor channel, or dopamine and serotonine transporters. The fluorescent properties, cellular uptake and confocal microscopy studies on 5d suggest a potential use of this probe to further clarify the molecular role of s2 receptor subtypes in normal and cancer cells.

Abstract Objectives A longer postoperative care, needed for patients admitted to the hospital, is expensive and associated with increased morbidity and mortality, when compared with the outpatient setting. Outpatient therapy with continuous infusion of drugs with elastomeric pumps represents an effective method to address this problem. The aim of this work is to analyse the benefits in using elastomeric devices and to test their their behaviour towards drugs to changes during storage that could influence quality, safety and efficacy of the therapy. Methods Several drugs belonging to different therapeutic classes, including anticancer, analgesic opioids, local anesthetics and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have been studied using a combined HPLC/LC-MS approach. Each drug was loaded in three different brands of elastomeric devices and the samples were withdrawn over 7 days and submitted to HPLC/LC-MS analyses. Key-Findings All tested drugs showed high stability in each filled device, in fact only a low variability, less than 5 %, in term of percentage change in chromatographic areas, was observed. Moreover additional peaks, due to degradation of drug and/or to medical device-drug interaction, have not been detected both in HPLC and LC-MS analysis. Conclusion Thanks to the implementation, within clinical protocols, of the use of these infusion systems, two important goals can be achieved: a) the keeping of the quality of care also out of hospitals and b) the reduction of tangible costs as well as intangible costs in health care.

A series of alkyloxyquinoline derivatives has been developed to evaluate the relationship between P-gp potency and lipophilicity. The results show a satisfactory lipophilicity-activity correlation although a series of derivatives showing higher P-gp potency is needed in order to confirm this hypothesis.

A set of basic aryl-group-containing compounds was synthesized with the aim of developing potent and selective P-glycoprotein (P-gp) modulators that are able to reverse multidrug resistance (MDR). The natures of the spacer (dicyclohexylamine or dialkylamine) and the aryl moieties were modified to investigate selectivity and the mechanism of P-gp interaction. The inhibitory activities of the compounds toward P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), the most relevant ATP binding cassette (ABC) transporters for MDR, were evaluated. The mechanism of P-gp interaction for each compound was investigated with three biological assays: apparent permeability (Papp ) determination (B→A/A→B) in Caco-2 cell monolayers, ATP cell depletion, and inhibition of Calcein-AM transport in MDCK-MDR1 cells. These assays allowed us to estimate the selectivity of the compounds for the three efflux pumps and to identify the structural requirements that define the P-gp-interaction profile. All dicyclohexylamine derivatives were found to be P-gp substrates, whereas one dialkylamine derivative was shown to be a P-gp inhibitor. The good MRP1 activity of one cis/cis isomer highlighted this as a lead candidate for the development of MRP1 ligands.

Introduction: P-glycoprotein (P-gp) plays a crucial role in beta-amyloid efflux from the blood–brain barrier thus becoming a promising pharmacological target in the treatment of Alzheimer's disease (AD). The increase of P-glycoprotein expression and activity by a P-gp inducer could be an effective pharmacological strategy in slowing or halting the progression of AD. Commonly used in vitro methods to classify a P-gp interacting molecule as substrate, inhibitor, modulator or inducer are not always confirmed by in vivo experiments. Here we validate the new dye-probe beta-amyloid (1–40) HiLyte Fluor™ TR-labeled (Ab-HiLyte) (Anaspec) P-gp mediated transport in the ex vivo rat everted gut sac assay by using MC18 or MC266, a fully characterized P-gp inhibitor and substrate, respectively, and compare it with the commonly used dye rhodamine. Methods: Male Wistar rats' everted intestines were divided into sacs, each sac was filled with 10 μM Ab-HiLyte with or without 50 μM of MC18 or MC266. Ab-HiLyte concentrations in mucosal fluid were measured spectrophotometrically at 594 nm at each appropriate time. Results: The Ab-HiLyte P-gp mediated efflux had a K=1.00×10−2 min−1 and t1/2=68.74 min, while in the presence of MC18, the Ab-HiLyte efflux turned out to be reduced by an order of magnitude (K=1.65×10−3 min−1) and the half life is extremely increased (t1/2=419 min). A P-gp substrate, likeMC266, determines no change in the efflux of Ab: the kinetic constant and the half life turned out to be unmodified (K=1.81×10−2 min−1 and t1/2=38.28 min). Discussion: The results demonstrate that the new dye probe, Ab-HiLyte, could be a probe of choice to unequivocally distinguish between a P-gp substrate and an inhibitor. This is particularly important as different groups obtain a controversial classification of the same compound.

Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with nonendogenous agonist induced activity (constitutive or basal activity). SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64%) and 136 nM (IA=-73%), respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively). The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h) and inverse agonists (SP-1e and SP1g) on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP-1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, espectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the heteroaromatic triazole as a core ring and a variety of chemical groups with different electronic features, size and shape on the catalytic activity of the two COX isoenzymes. The new triazoles were synthesized in fair to good yields and then evaluated for their inhibitory activity towards COXs arachidonic acid conversion catalysis. Their COXs selectivity was also measured. A predictive pharmacometric Volsurf plus model, experimentally confirmed by the percentage (%) of COXs inhibition at the concentration of 50 μM and IC50 values of the tested compounds, was built by using a number of isoxazoles of known COXs inhibitory activity as a training set. It was found that two compounds {4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) and 4-[1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-yl]benzenamine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 Combining double low line 15 and 3 μM, respectively) and that the presence of a methylsulfamoyl group (SO2CH3) is not a rule to have a Coxib. In fact, 4-(4-methoxyphenyl)-5-methyl-1-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazole (23) has COX-1 IC50 Combining double low line 23 μM and was found inactive towards COX-2.

The use of microorganism growing cells is a well recognized methodology in biocatalyzed organic reactions. A non-conventional thermotolerant Kluyveromyces marxianus yeast strain was used for the bioreduction of different arylketones. Differently substituted ketones were converted into the corresponding (S)-alcohols with up to 96% enantiomeric excess under very mild reaction conditions. Kluyveromyces marxianus represents a promising biocatalyst for the production of optically active 1-arylethanols.

P-glycoprotein (P-gp) is involved in MDR and in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD) and epilepsy. Cytochrome P450 enzymes (CYP450(s)) catalyze the metabolism of a wide variety of endogenous and exogenous compounds including xenobiotics, drugs, environmental toxins, steroids, and fatty acids. P-gp substrates, inhibitors and inducers should be designed and developed studying interacting mechanism with both P-gp an CYP450 enzymes before they could be employed in MDR and/or in neurodegenerative disorders. Here, the ex vivo rat everted gut sac assay has been proposed as an immediate approach to simultaneously study metabolism and transport of drugs. Elacridar, verapamil and cyclosporine A (CsA), P-gp inhibitor, substrate and modulator respectively, have been tested to validate this ex vivo approach. The new model have been used yet to develop our ligands MC18, MC266 and MC80, both as potential drugs for MDR and radiotracers for diagnosis of neurodegenerative disorders. Herein, a comparative evaluation of transport and metabolic results, by using in vitro, ex vivo and in vivo assays, is reported.

INTRODUCTION: Stimulation of the β(3)-adrenoceptor (β(3)-AR) is thought to be a valuable approach for the treatment of obesity, type 2 diabetes, heart failure, frequent urination, preterm labor, anxiety and depression. Therefore, the β(3)-AR is recognized as an attractive target for drug discovery. Simultaneous activation of the β(1)- and β(2)-AR can cause undesirable side effects such as increased heart rate and muscle tremors. Consequently, much effort has been directed towards the design and development of selective β(3)-AR agonists through original synthetic chemistry, extensive in vitro tests and detailed preclinical investigations to various phases of clinical trials. AREAS COVERED: SciFinder Scholar, PubMed, ISI web of Knowledge(SM), Espacenet, ClinicalTrials and Google have been used as the main sources for retrieving literature and patents filed since the discovery of β(3)-AR through to June 2010. This review discusses the enormous efforts made by private and public research laboratories to uncover β(3)-AR ligands and to prove their usefulness as drugs. EXPERT OPINION: Remarkable knowledge has been gained about the physio-pathological role of the β(3)-AR to date. Many highly potent and selective β(3)-AR ligands (agonists, antagonists and inverse agonists) have been discovered; however, further investigations are still needed to identify novel compounds acting as β(3)-AR ligands in order to adequately treat the diseases in which β(3)-AR is involved.

The present invention relates to novel pyrazoles which are potent and selective inhibitors of cyclooxygenase-1 (COX-1) and to their radiolabeled derivatives thereof which are both useful as theranostics of a number of pathologies.

COX-1 plays a previously unrecognized part in the neuroinflammation. Genetic ablation or pharmacological inhibition of COX-1 activity attenuates the inflammatory response and neuronal loss. In this context, the effects of selective COX-1 inhibitors (P6, P10, SC-560, aspirin) and coxibs (celecoxib and etoricoxib) on LPS-stimulated microglial cell function (a worldwide accepted neuroinflammation model) were investigated, and the effects on COX-1/COX-2, cPGES mRNA and iNOS expression, PGE2 and NO production and NF-kB activation by IkBalpha phosphorylation were evaluated. The total suppression of the expressionof both COX-1 and COX-2 by their respective selective inhibitors occurred. NF-kB remained almost completely inactive in the presence of coxibs, as expected, and totally inactive in the presence of P6. P6 also markedly counteracted LPS enhancing cPGES mRNA expression and PGE2 production. Since COX-1 is predominantly localized in microglia, its high selective inhibition rather than COX-2 (by coxibs) is more likely to reduce neuroinflammation and has been further investigated as a potential therapeutic approach and prevention in neurodegenerative diseases with a marked inflammatory component.

Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3- (5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([18/19F]-P6) is the most promising derivative [IC50 ¼ 2.0 mM (purified oCOX-1) and 1.37 mM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[18F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K18F/Kryptofix 2.2.2 complex, that afforded [18F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [18F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [18F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.

3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4-diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure−activity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of 5-methyl (or -CF3), 4-phenyl, and 5-chloro(-bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1-dependent thromboxane (TX) A2. Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet-derived TXA2 over protective vascular-derived prostacyclin (PGI2).

Compounds 8a–d have been designed as bioisosters of tariquidar for imaging P-gp expression and density by PET. The results displayed that compounds 8b and 8d could be considered potential P-gp/BCRP ligands suitable as 11C and 18F radiotracers, respectively.

Starting from the previously developed P-gp ligands 1a and 1b (EC50 ¼ 0.25 mM and 0.65 mM, respectively), new arylmethyloxyphenyl derivatives have been synthesized as P-gp modulators in order to investigate: (i) the effect of small electron-donor groups (OMe) (5e11), (ii) the effect of the replacement of methoxy groups with an electron-withdrawal substituent (Cl) on C-ring (13) (iii) the effect induced by the replacement of C-ring with heteroaromatic cycles such as thiophene and pyrimidine (13, 15, 16), (iv) the effect induced by molecular constriction on C ring (14, 17, 18) on P-gp modulating activity. The results demonstrated that P-gp inhibition potency is strongly correlated to the number of methoxy groups in the A-ring whereas the methoxylation of C-ring seems to poorly affect P-gp activity. The best result was found for compound 10 that displays a nanomolar affinity (EC50 ¼ 7.1 nM) towards P-gp pump and, in the meantime lacks of activity against MRP1 pump.

The development of P-glycoprotein (P-gp) ligands remains of considerable interest mostly for investigating protein structure and transport mechanism. In the last years many ligands, belonging to different generations, have been tested for modulating P-gp activity. Aim of the present work is to perform SAR studies on tetrahydroisoquinoline derivatives in order to design potent and selective P-gp ligands. For this purpose the effect of bioisosteric replacement and the role of flexibility have been investigated and four series of tetrahydroisoquinoline ligands have been developed: a) 2-aryoxazole bioisosteres; b) elongated analogues; c) 2H-Chromene and d) 2-biphenyl derivatives. Obtained results showed that both 2-biphenyl derivative 20b and elongated derivative 6g behaved as strong P-gp substrates. In conclusion important items have been highlighted for developing potent and selective P-gp ligands providing a solid starting point for further optimization.

Since cyclooxygenase (COX) isozymes discovery, many papers and reviews have been published to describe the structural bases of COX inhibition, and to debate on the therapeutic and adverse effects of worldwide clinically used nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective inhibitors (well known as Coxibs). COX-2 inhibition has been widely investigated, whereas the role of COX-1 in human pathophysiology is mostly not yet well ascertained. As time goes on, the cliché that the constitutively expressed isoform COX-1 is only involved in normal physiological functions, such as platelet aggregation, gastric mucosa protection and renal electrolyte homeostasis is going to be shattered. Low-dose aspirin, behaving as a preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by this isoenzyme in many mammalian cell types. This review would elucidate the most recent findings on selective COX-1 inhibition and their relevance to human pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain. It would also focus on the design and development of new highly selective COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a deeper insight of the role of COX-1 in human health and disease. Among the traditional NSAIDs, other then aspirin and indomethacin, only few examples of selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have been so far identified. This review has also the scope to stimulate the development of novel drugs, which activity is COX-1 mediated.

Background/Aims: Gastrointestinal damage (GD) is commonly associated with the inhibition of cyclooxygenase (COX)-1, one of the two known COXs, by traditional non-steroidal anti-inflammatory drugs. More recent evidences have proven that GD is caused by the simultaneous inhibition of the two COXs. This study was designed to evaluate the effect of the selective COX-1 inhibition on gastric integrity. Methods: GD was evaluated in male CD1 mice. Drugs were administered by gastric gavage at a dose of 50 mg/kg (injection volume of 100 μl). Control mice received an equal volume of the vehicle (10% ethanol). Each mouse, in groups of at least 6 mice, received one dose/day for 5 days. Results: In Western blot analysis, COX-1 expression levels were found to be significantly reduced in mice treated with 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) in comparison to mice pretreated with aspirin (ASA), which exhibited higher levels of COX-1, thus confirming the high selectivity of P6 towards COX-1 enzyme inhibition. Mucosal sections obtained from ASA-treated mice showed breaks in the epithelial barrier and a marked alteration of foveolae and gastric glands, whereas stomachs isolated from mice sacrificed after 5 days of chronic administration of P6 (at a dose of up to 50 mg/kg/day) showed sporadic transient mucosal hyperemia and did not seem to display any significant gastric damage. Conclusions: The selective COX-1 inhibition by P6 does not cause gastric damage in mice but preserves mucosal integrity.

Background: Nor-BNI, GNTI and JDTic induce selective k opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. Results: In binding assays, the three antagonists showed no detectable affinity (Ki$10 mM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for k opioid receptors, with moderate selectivity over m and d (3 to 44-fold). Nor-BNI bound weakly to the a2C-adrenoceptor (Ki = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the a1A-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M1 receptor antagonist (KB = 3.7 mM). JDTic bound to the noradrenaline transporter (Ki = 54 nM), but only weakly inhibited transport (IC50 = 1.1 mM). JDTic also bound to the opioid-like receptor NOP (Ki = 12 nM), but gave little antagonism even at 30 mM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of a1A-adrenoceptors). This may contribute to GNTI’s severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, k opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective k opioid antagonists.

Microglia, the immune cells of the brain, are one of the key mediators of neuroinflammation. Microglial activation leads these cells to produce various proinflammatory and neurotoxic substances. Several in vitro and in vivo studies have demonstrated that a decrease in the levels of pro-inflammatory mediators in microglia can attenuate the severity of neuro-degenerative diseases, including AD, PD, ALS, MS and Huntington’s disease. Thus, regulation of excessive microglial activation should be of therapeutic value especially in neuro-degenerative disorders. Cyclooxygenase(COX) is a key enzyme in the conversion of arachidonic acid into prostaglandins and other lipid mediators. It is widely accepted that this enzyme play a pivotal role in the neuro-inflammatory process exacerbation. Two COX isoforms are known: COX-1, constitutively expressed in most tissues, classically considered as the isoform primarily responsible for maintaining the homeostasis by mediating physiological responses, and COX-2, which represents the inducible form, mainly activated in response to inflammatory stimuli. In this respect, recent studies have also indicated a previously unrecognized pro-inflammatory role of COX-1 in the pathophysiology of acute and chronic neurological disorders. Consequently, it was reconsidered the potential beneficial effect of COX-1 inhibition in the treatment of neuroinflammation [1]. These findings prompted us to investigate the behaviour of two selective COX-1 inhibitors such as P6 (COX-1 IC50= 0.5 mM and COX-2 IC50 >100 mM) and P10 (COX-1 IC50= 0.09 mM and COX-2 IC50 = 2.49 mM) [2] in an in vitro experimental model of inflammation, represented by mouse N13 microglial cells activated by lipopolysaccharide (LPS) [3]. LPS is a component of the outer cell wall of gramnegative bacteria and is well known as an inducer of inflammatory responses. New selective COX-1 inhibitors are here proposed also as useful tools in pharmacological studies to investigate the role of COX-1 isoenzyme in neuroinflammation or more in general in all the investigations in which only COX-1 needs to be selectively inhibited. The results of this study as well as their rationale will be presented and discussed. References: 1. Perrone, M.G.; Scilimati, A.; Simone, L., Vitale, P. Curr. Med. Chem.2010,17, 3769-805. 2. Di Nunno. L., Vitale, P., Scilimati, A., Tacconelli, S.; Patignani, P. J. Med. Chem. 2004, 47, 4881-90. 3. Calvello, R.; Panaro, M.A.; Carbone, M.L.; Cianciulli, A.; Perrone, M.G.; Vitale, P.; Malerba, P.; Scilimati, A. Biochem. Pharmacol.,2011, submitted for publication.

Inhibition of drug efflux pumps such as P-glycoprotein (P-gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N-substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of Pgp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P-gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene- 1-yl analogue (R)-2-[(2,3-dichlorophenoxy)methyl]-1- (naphthalen-1-ylmethyl)pyrrolidine) [(R)-7a] emerged foremost for its potency and stereoselectivity toward P-gp, with the S enantiomer being nearly inactive. The modulation of P-gp by (R)-7a involved consumption of ATP, thus demonstrating that the compound behaves as a P-gp substrate.

The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.

The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo. The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70. Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav 1.2 channel current (ICa1.2 ) of A7r5 cells were studied. At concentrations >10 μM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1-100 μM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67-14.49 μM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K(+) (K60)-induced responses. In rings cultured for 7 days with both compounds (1-10 μM), 10 μM MC70 significantly reduced, while 10 μM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1-100 μM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 μM, respectively. These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.

La presente invenzione riguarda composti eterociclici di formula generale (II) che sono ligandi del recettore adrenergico beta-3 e il loro uso in terapia.

La presente invenzione si riferisce a nuovi eterocicli che sono inibitori potenti e selettivi della cicloossigenasi-1 (COX-1) e ai loro derivati ​​radiomarcati che sono entrambi utili come teranostici di un certo numero di patologie.

L'invenzione riguarda una nuova classe di composti di formula (I) indirizzati a COX-1. L'invenzione riguarda anche l'uso di alcuni di tali composti come uno strumento per studiare la struttura e la funzione dell'enzima, nel trattamento mirato alla COX-1 o al rilevamento di COX-1 in disturbi o malattie correlate come il cancro e la neuroinfiammazione, in particolare in neurologico (es. disturbi dello spettro autistico) e malattie neurodegenerative (es Malattie di Alzheimer, Malattia di Parkinson, sclerosi laterale amiotrofica (SLA), sclerosi multipla (SM), trauma cranico (TBI), demenza da HIV e malattie da prioni) e nel tumore ginecologico (es. Cancro ovarico), tumore del collo e della testa e ematologico tumori (ad esempio mieloma multiplo) e nella rilevazione di COX-1 in "in vitro" (cellule e tessuti) e in "in vivo".

The present invention relates to novel heterocycles which are potent and selective inhibitors of cyclooxygenase-1 (COX-1) and to their radiolabeled derivatives thereof which are both useful as theranostics of a number of pathologies.

The present invention relates to new compounds, ligands of the beta-3 adrenergic receptor, their preparation and their use in therapy or as research tools for said receptor; the invention also relates to a process for the preparation of the compounds of the invention and the use of inverse agonists of the beta-3 adrenergic receptor as medicaments.

The present invention refers to a method and a kit of screening for therapeutic compounds useful in detoxifying central nervous system from ß-amyloid peptide. The method and kit involve the use of the beta amyloid peptide in the everted gut sac assay and allow assessing the inducing activity of the test compounds on the P-gp-mediated ß-amyloid peptide transport