Tapio Nevalainen | University of Eastern Finland (original) (raw)

Papers by Tapio Nevalainen

Magnetic Resonance in Chemistry, 1994

The 1H NMR spectra of 64 polychlorinated diphenyl ethers (PCDEs) were measured and assigned. Mult... more The 1H NMR spectra of 64 polychlorinated diphenyl ethers (PCDEs) were measured and assigned. Multiple linear regression analysis was used to estimate the effects of chlorine atoms on the 1H NMR chemical shifts and coupling constants. The ‘simple sum rules’ were found to be inadequate for the prediction of 1H NMR chemical shifts of PCDEs. Therefore, corrective terms of two chlorine atoms were taken into account. The most important effects on chemical shifts were shown to be the steric interactions of two adjacent chlorine atoms and the intramolecular ring current effect observed in the ortho-proton of tri-ortho-substituted PCDEs. The substituent effects on J(HH) coupling constants were found to be approximately additive. An interannular coupling between ortho-protons [6J(HH) = 0.05–0.15 Hz] of adjacent rings was observed.

Magnetic Resonance in Chemistry, 1993

The 13C NMR chemical shifts and coupling constants for diphenyl ether and 28 environmentally inte... more The 13C NMR chemical shifts and coupling constants for diphenyl ether and 28 environmentally interesting polychlorinated diphenyl ethers were measured and analysed.

Environmental Toxicology and Chemistry, 1994

Electronic properties of polychlorinated dibenzo p dioxins (PCDDs), polychlorinated dibenzofurans... more Electronic properties of polychlorinated dibenzo p dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), poly chlorinated biphenyls (PCBs), and polychlorinated diphenyl ethers (PCDEs) were calculated using the semi-empirical AM 1 method The calculated electronic descriptorsthe energy of the lowest unoccupied molecular orbital (ELUMO), the energy of the highest occupied molecular orbital (EHOMO), the ELUMO-EHOMO gap (@), and molecular polarizability-are related to the Ah re ceptor binding affinity values of PCDDs, PCDFs, and PCBs and immunotoxicity values for PCDEs The quantitative structure activity relationships (QSARs) based on chlorine substitution patterns were also constructed, and they proved to be very predictive for Ah receptor binding Significant correlations of the electronic factors were found between the dE and Ah receptor binding affinities for PCDDs, PCDFs, and PCBs and for immunotoxicity of PCDEs A combination of descriptors EL,,, and the total number of chlorine atoms attached to a molecule (nci) gives significant correlation for the Ah receptor binding of PCDFs and for immunotoxicity of PCDEs Hydrophobicity values taken from the literature were shown to be nonsignificant for toxicity prediction of these polychlorinated compounds

Journal of Medicinal Chemistry, 2008

A series of commercial phenyl-, heteroaryl-, alkyl-, and alkenylboronic acids were evaluated for ... more A series of commercial phenyl-, heteroaryl-, alkyl-, and alkenylboronic acids were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC50 in the nanomolar or low-micromolar range. Eight of these compounds inhibited MGL with IC50 in the micromolar range. The most potent compound, phenylboronic acid with para-nonyl substituent (13), inhibited FAAH and MGL with IC50 of 0.0091 and 7.9 µM, respectively.

Biomacromolecules, 2005

An efficient synthetic route was developed for the mild chloroacylation of chitosan with differen... more An efficient synthetic route was developed for the mild chloroacylation of chitosan with different chloroacyl chlorides. Full N-chloroacylation was obtained with this procedure without any O-acylation, and products having lower degrees of substitution can also be produced. Organo-soluble 6-O-triphenylmethylchitosan was used as a starting material for the acylation reactions. The resulting N-chloroacyl-6-O-triphenylmethylchitosan intermediates were also organo-soluble and characterized by FT-IR. N-Methylpiperazine moieties were attached to make end products that were sufficiently soluble for characterization by NMR and also to prove that the present intermediates could be used for further modifications. The end products were fully characterized by 1 H NMR, 13 C NMR, and 2D 1 H-13 C heteronuclear single-quantum correlation NMR spectroscopy. The degrees of substitution were determined by 1 H NMR. Molecular weight determination by GPC-LS displayed a significant degradation of the polymer. The weight-average molar masses (M w ) of the end products ranged from 29.6 to 49.4 kDa, when the M w of the starting material was 144.2 kDa.

European Journal of Pharmaceutical Sciences, 2000

Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro... more Novel morpholinyl (4a) and piperazinylalkyl (4b-e) esters were synthesized and evaluated in vitro for their properties as bioreversible topically administered dermal prodrugs of naproxen. These ionizable prodrugs exhibited various aqueous solubilities and lipophilicities, depending on the pH of medium. As indicated by octanol-buffer partition coefficients (logP(app)) at pH 7.4, all of the prodrugs were significantly more lipophilic (logP(app)=0.7-3.9) than naproxen (logP(app)=0.3). Furthermore, the most aqueous of the soluble prodrugs (4b-d) were only 2-3-fold less soluble in an aqueous buffer of pH 7.4 ( approximately 30-50 mM) than was naproxen ( approximately 100 mM). At a pH of 5.0, prodrugs showed a generally higher aqueous solubility and similar logP(app) values, compared to naproxen. The chemical and enzymatic hydrolysis of prodrugs at 37 degrees C was investigated in aqueous buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs showed moderate chemical stability (t(1/2)=15-150 days at pH 5.0), and they were hydrolyzed enzymatically to naproxen, with half-lives ranging from 0.4 to 77 min. In permeation studies using post-mortem human skin in vitro, the flux of naproxen was 6.5 and 1.6 nmol/cm(2). h in a saturated aqueous buffer vehicle of pH 7.4 and 5.0, respectively. Among the prodrugs, two piperazinyl derivatives (4c and 4d) resulted in a 9- and 4-fold enhancement of permeation, respectively, when compared to naproxen itself at pH 7.4. 4c also resulted in a significantly (4-fold) better permeation than naproxen at pH 5.0. In conclusion, piperazinyl esters improved skin permeation of naproxen and are promising prodrugs of naproxen for topical drug delivery.

Pharmaceutical Research, 1999

Purpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and... more Purpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. Methods. The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. Results. The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log Papp) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t1/2 = 4−19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-mshowed poor aqueous solubility and permeation across the skin. Conclusions. Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.

Tetrahedron Letters, 2002

An efficient and simple synthesis is described for the production of various chloromethyl phospha... more An efficient and simple synthesis is described for the production of various chloromethyl phosphates as useful reagents for the preparation of phosphonooxymethyl prodrugs.

Journal of Pharmaceutical Sciences, 1998

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as t... more A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.

Journal of Medicinal Chemistry, 2007

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydro... more Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

Bioorganic & Medicinal Chemistry Letters, 2000

AbstractÐEntacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate... more AbstractÐEntacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate ester. The phosphate promoiety increased aqueous solubility of the parent drug by more than 1700-and 20-fold at pH 1.2 and 7.4, respectively. The phosphate ester provides adequate stability (t 1/2 =2227 h; pH 7.4) towards chemical hydrolysis, and allowed for release of the parent drug via enzymatic hydrolysis in liver homogenate. #

Chemistry & Biology, 2005

We have previously reported that the endocannabinoid, 2-arachidonoyl-glycerol (2-AG), is hydrolyz... more We have previously reported that the endocannabinoid, 2-arachidonoyl-glycerol (2-AG), is hydrolyzed in rat cerebellar membranes by monoglyceride lipase (MGL)-like enzymatic activity. The present study shows that, like MGL, 2-AG-degrading enzymatic activity is sensitive to inhibition by sulfhydryl-specific reagents. Inhibition studies of this enzymatic activity by N-ethylmaleimide analogs revealed that analogs with bulky hydrophobic N-substitution were more potent inhibitors than hydrophilic or less bulky agents. Interestingly, the substrate analog N-arachidonylmaleimide was found to be the most potent inhibitor. A comparison model of MGL was constructed to get a view on the cysteine residues located near the binding site. These findings support our previous conclusion that the 2-AG-degrading enzymatic activity in rat cerebellar membranes corresponds to MGL or MGL-like enzyme and should facilitate further efforts to develop potent and more selective MGL inhibitors.

Journal of Medicinal Chemistry, 2006

The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2dih... more The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2dihydroquinoline-3-carboxylic acid N-benzo dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and effective CB2 receptor inverse agonists. A series of aromatic amides of 7-methoxy-2-oxo-8pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 6 was synthesized, and the CB2 receptor activities of the compounds were determined by a [ 35 S]GTP γ S-binding assay using membranes of CHO cells stably transfected with the human CB2 receptor. As a result, all the compounds were defined as full CB2 receptor inverse agonists, and additionally, except for two 3,4-dihydroxyphenylalkylamides, they were found to be equally potent as SR144528.

Journal of Medicinal Chemistry, 2004

Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structur... more Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 µg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or lowmicromolar ED 50 activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.

Journal of Medicinal Chemistry, 2002

A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to... more A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t 1/2 ) 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t 1/2 ) 7 min; pH 7.4) at 37°C. The therapeutical potential of this novel codrug is discussed.

Chemistry & Biology, 2006

Previous studies indicate that in brain tissue the endocannabinoid 2-AG is inactivated by monogly... more Previous studies indicate that in brain tissue the endocannabinoid 2-AG is inactivated by monoglyceride lipase (MGL)-catalyzed hydrolysis, and a recent report has indicated that MGL activity could be specifically inhibited by URB754 [1]. In the present study, URB754 failed to inhibit 2-AG hydrolysis in rat brain preparations. In addition, brain cryosections were employed to assess whether URB754 could facilitate the detection of 2-AG-stimulated G protein activity. Nevertheless, whereas pretreatment with PMSF readily allowed detection of 2-AG-stimulated G protein activity, URB754 was ineffective. In contrast to previous claims, brain FAAH activity was also resistant to URB754. Thus, in our hands URB754 was not able to block the endocannabinoid-hydrolyzing enzymes and cannot serve as a lead structure for future development of MGL-specific inhibitors.

Journal of Medicinal Chemistry, 2005

To identify novel selective CB2 lead compounds, a comparative model of the CB2 receptor was const... more To identify novel selective CB2 lead compounds, a comparative model of the CB2 receptor was constructed using the high-resolution bovine rhodopsin X-ray structure as a template. The CB2 model was utilized both in building the database queries and in filtering the hit compounds by a docking and scoring method. In G-protein activation assays, 1-isoquinolyl[3-(trifluoromethyl)phenyl]methanone (40, NRB 04079) was found to act as a selective agonist at the human CB2 receptor.

European Polymer Journal, 2007

The purpose of this study was to synthesize series of methylated chitosaccharide derivatives, pos... more The purpose of this study was to synthesize series of methylated chitosaccharide derivatives, possessing various degree of methylation, and to determine their structure activity relationship (SAR) with regard to their antibacterial effect against Staphylococcus aureus. Chitosan polymer and chitooligomers were used as starting materials and were methylated by reaction with methyl iodide. Depending on the reaction conditions the degree of

Carbohydrate Polymers, 2006

... and Tsai and Su, 1999). The antimicrobial activity of chitosan increases with decreasing pH (... more ... and Tsai and Su, 1999). The antimicrobial activity of chitosan increases with decreasing pH (Jeon et al., 2001, No et al., 2002, Roller and Covill, 1999, Tsai and Su, 1999, Wang, 1992 and Yang et al., 2005). This is due to the ...

Life Sciences, 2000

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueou... more Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N -alkyl and N,Ndialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N -alkyl and N,N -dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t 1/2 ϭ 14.9Ð 20.7 h), but hydrolyzed rapidly (t 1/2 ϭ 0.8Ð2.7 h) in human serum. However, in contrast to N -alkyl carbamates, N,N -dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N -Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N -alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.