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PubMed2004

5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha4beta2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential probes for imaging with positron emission tomography.

Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from -1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at alpha4beta2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[(18)F]fluoro-5-(pyridin-3-yl)-A-85380 ([(18)F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[(18)F]fluoropyridin-5-yl)pyridine) ([(18)F]35), were radiolabeled with (18)F. Comparison of PET data for [(18)F]31 and 2-[(18)F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [(18)F]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[(18)F]FA. Therefore, [(18)F]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

Animals↗
PubMed2006

Regioselective synthesis of 3-(2-hydroxyaryl)pyridines via arynes and pyridine N-oxides.

A variety of substituted 3-(2-hydroxyphenyl)pyridines have been prepared regioselectively by a transition-metal-free, mild, one-step route, which involves the reaction of pyridine N-oxides with silylaryl triflates in the presence of CsF in acetonitrile at room temperature. These reactions proceed in good yields through what appears to be a series of rearrangements.

Indicators and Reagents↗
PubMed2005

Structural diversity in iron(II) complexes of 2,6-di(pyrazol-1-yl)pyridine and 2,6-di(3-methylpyrazol-1-yl)pyridine.

The syntheses, magnetochemistry and crystallography of [Fe(L1)2]I0.5[I3]1.5 (1), [Fe(L1)2][Co(C2B9H11)2]2 (2) and [Fe(L2)2][SbF6]2 (3) (L1 = 2,6-di(pyrazol-1-yl)pyridine; L2 = 2,6-di(3-methylpyrazol-1-yl)pyridine) are described. Compounds 1 and 3 are high-spin between 5-300 K. For 1, this reflects a novel variation of an angular Jahn-Teller distortion at the iron centre, which traps the molecule in its high-spin state. No such distortion is present in 3; rather, the high-spin nature of this compound may reflect ligand conformational strain caused by an intermolecular steric contact in the crystal lattice. Compound 2 exhibits a gradual high --> low spin transition upon cooling with T(1/2) = 318 +/- 3 K, that is only 50% complete. This reflects the presence of two distinct, equally populated iron environments in the solid. One of these unique iron centres adopts the same angular structural distortion shown by 1 and so is trapped in its high-spin state, while the other, which undergoes the spin-crossover, has a more regular coordination geometry. In contrast with 3, the solvated salts [Fe(L2)2][BF4]2 x 4 CH3CN and [Fe(L2)2][ClO4]2 x (CH3)2CO both undergo gradual thermal spin-transitions centred at 175 +/- 3 K.

Cations↗
PubMed1974

Microbial metabolism of the pyridine ring. The hydroxylation of 4-hydroxypyridine to pyridine-3,4-diol (3,4-dihydroxypyridine) by 4-hydroxypyridine-3-hydroxylase.

1. The first metabolic step in the biodegradation of 4-hydroxypyridine by an Agrobacterium sp. was hydroxylation to form pyridine-3,4-diol. 2. Extracts required 1mol of O(2) and 1mol of NADH or NADPH for the conversion of 4-hydroxypyridine into pyridine-3,4-diol, suggesting that the enzyme responsible, 4-hydroxypyridine-3-hydroxylase, was a mixed function mono-oxygenase. 3. After treatment with acidic (NH(4))(2)SO(4) the enzyme required FAD for activity; FMN and riboflavin would not substitute for FAD. 4. The rate of anaerobic reduction of FAD by NAD(P)H was increased more than tenfold in the presence of 4-hydroxypyridine, suggesting that the mechanism of hydroxylation was similar to that of other aromatic hydroxylases which are of the mono-oxygenase type. 5. The partially purified enzyme was extremely specific for its heterocyclic substrate but would utilize either NADH or NADPH. 6. 4-Hydroxypyridine-3-hydroxylase was strongly inhibited by high substrate concentration (above 0.5mm) especially below pH7.5. 8. The inflexion at pH8.4 in a pK(m) versus pH plot, together with strong inhibition by p-chloromercuribenzoate, suggested a role for thiol groups in substrate binding.

Ammonium Sulfate↗
PubMed2001

Selective amination of secoiridoid glycosides to give monomeric pyridine, dimeric pyridine, and naphthyridine alkaloids.

Treatment of the secoiridoids oleuropein (4), ligstroside (5) and methyloleoside (6) by beta-D-glucosidase in the presence of ammonium chloride led exclusively to monomeric pyridine alkaloids 7, 1, and 8. Dimeric 3,4,5-trisubstituted pyridines were obtained from methyloleoside (6) when ammonium chloride was generated in the reaction mixture by successive additions of ammonia and hydrochloric acid. The use of ammonium acetate permitted conversion of secoiridoids 4 and 5 into the naphthyridine alkaloid jasminine (3).

Alkaloids↗
PubMed2005

In vivo characterization of the novel imidazopyridine BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a potent and highly selective inhibitor of inducible nitric-oxide synthase.

Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tested the in vivo potency of BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo-[4,5-b]pyridine], a selected member of this inhibitor class, in three different rat models of lipopolysaccharide-induced systemic inflammation. Delayed administration of BYK191023 dose-dependently suppressed the lipopolysaccharide-induced increase in plasma nitrate/nitrite (NO(x)) levels with an ED(50) of 14.9 micromol/kg/h. In a model of systemic hypotension following high-dose lipopolysaccharide challenge, curative administration of BYK191023 at a dose that inhibited 83% of the NO(x) increase completely prevented the gradual decrease in mean arterial blood pressure observed in vehicle-treated control animals. The vasopressor effect was specific for endotoxemic animals since BYK191023 did not affect blood pressure in saline-challenged controls. In addition, in a model of lipopolysaccharide-induced vascular hyporesponsiveness, BYK191023 infusion partially restored normal blood pressure responses to norepinephrine and sodium nitroprusside via an l-arginine competitive mechanism. Taken together, BYK191023 is a member of a novel class of highly isoform-selective iNOS inhibitors with promising in vivo activity suitable for mechanistic studies on the role of selective iNOS inhibition as well as clinical development.

Animals↗
PubMed2005

The novel imidazopyridine 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) is a highly selective inhibitor of the inducible nitric-oxide synthase.

We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NO synthases at 86 nM, 17 microM, and 162 microM, respectively. Inhibition of inducible NO synthase was competitive with l-arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. In radioligand and surface plasmon resonance experiments, BYK191023 exhibited an affinity for iNOS, nNOS, and eNOS of 450 nM, 30 microM, and >500 microM, respectively. Inhibition of cellular nitrate/nitrite synthesis in RAW, rat mesangium, and human embryonic kidney 293 cells after iNOS induction showed 40- to 100-fold higher IC(50) values than at the isolated enzyme, in agreement with the much higher l-arginine concentrations in cell culture media and inside intact cells. BYK191023 did not show any toxicity in various rodent and human cell lines up to high micromolar concentrations. The inhibitory potency of BYK191023 was tested in isolated organ models of iNOS (lipopolysaccharide-treated and phenylephrine-precontracted rat aorta; IC(50) = 7 microM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC(50) > 100 microM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC(50) > 100 microM). These data confirm the high selectivity of BYK191023 for iNOS over eNOS and nNOS found at isolated enzymes. In summary, we have identified a new highly selective iNOS inhibitor structurally unrelated to known compounds and l-arginine. BYK191023 is a valuable tool for the investigation of iNOS-mediated effects in vitro and in vivo.

Animals↗
PubMed2001

mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors.

The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- and N-methyl-D-aspartate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricular administration of MPEP to rats markedly improved motor recovery and reduced deficits of spatial learning after lateral fluid percussion-induced traumatic brain injury. Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.

Animals↗
PubMed1993

Pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo- [2',1':2,3]imidazo[4,5-c]pyridines and pyrrolo[2,1-f]purines as potential benzodiazepine ligands.

The synthesis of some 7,8,8a,9-tetrahydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridin-6-ones, 5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8-ones and 7,8,8a,9-tetrahydro-6H-pyrrolo[2,1-f]purin-6-ones is reported. The structure of the obtained compounds has been assigned by means of 1H-NMR spectra assisted by NOESY measurements. In addition, the ability to displace [3H]-flunitrazepam binding from rat brain membranes is determined. Only the pyrrolopurine derivative 5d binds to the benzodiazepine receptor (BZR) with appreciable potency.

Animals↗
PubMed1993

[Synthesis of thieno(2,3-b)pyridines with oxalamidic acid or an oxalamidic alkylester residues and of 4-alkoxy-pyrido(3',2':4,5)thieno(3,2-d)pyridine-2-carboxylic acid derivates].

N-(2-Alkoxycarbonyl-thieno[2,3-b]pyrid-3-yl)oxalamide acid alkylester B were synthesized by the reaction of 3-amino-2-carboxylic esters A with oxalic acid diethylester in presence of sodium alkoxides. The 3-amino-2-cyano-thieno[2,3-b]pyridines C yielded under the same conditions via the N-(2-cyano-thieno[2,3-b]pyrid-3-yl)oxalamidic acid alkylesters D/1-D/4 the 4-alkoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2-carboxylic acid alkylesters E/1-E/8. The compounds D/1, D/2 and E/1-E/5 were hydrolyzed to give the corresponding carboxylic acids. The 3-amino-furo[2,3-b]pyridine-2-carboxylic acid ethylester H reacted with oxalic ethylester chloride to give the oxalamide ethylester I. The synthesized substances showed an antinaphylactic activity.

Animals↗
PubMed2001

Comproportionation reaction and hindered rotation of coordinated pyridine rings in an acetate-bridged tetraplatinum(II) cluster with pyridine-based ligands in the cluster plane.

A series of pyridine-substituted derivatives of octaacetatotetraplatinum(II), [Pt4(CH3COO)8-n(L)2n]n+ (L= 4-dimethylaminopyridine (dmap), pyridine (py), 4-cyanopyridine (cpy); n = 1-4) were prepared, and the tetra- and octasubstituted forms (n = 2 and 4) were isolated. 1HNMR spectra showed that this type of cluster undergoes a comproportionation reaction. Reactions between clusters in which n = 0 and 2, n = 0 and 4, and n = 2 and 4 afforded Pt4 clusters with n = 1, 2, and 3, respectively, as a main product in acetonitrile. The dmap-substituted clusters, trans-[Pt4(CH3COO)6(dmap)4](ClO4)2 x 3CH3NO2 (3a(ClO4)2 x 3CH3NO2) and [Pt4(CH3COO)4(dmap)8](ClO4)4 x 4 H2O (5a(ClO4)4-4H2O), have been structurally characterized. Both 3a and 5a have a square-planar cluster core comprised of four PtII ions, and all eight out-of-plane coordination sites are occupied by acetate ligands in a bridging mode. In 5a, all of the in-plane sites are occupied by dmap ligands. In 3a, four dmap ligands occupy the coordination sites at the two mutually opposite edges of the square planar cluster skeleton, giving a trans tetrasubstituted form of [Pt4(CH3COO)8-] (1). In octasubstituted 5a, adjacent dmap ligands are so closely arranged that the Pt-N distances (2.20(3), 2.30(3) A) are longer than those in tetrasubstituted 3a (2.13(1), 2.15(1) A) and related Pt4 clusters. Furthermore, rotation of the dmap ligand about the Pt-N bond in 5a was restricted, and the rate constant of the rotation was 4.5s(-1) at 20 degrees C from dynamic NMR study. Cluster [Pt4(CH3COO)5(dmap)6]3+ (4a) also exhibited similar hindered rotation with the rate constants of 2.0s(-1), 12s(-1) and approximately 10(4)s(-1) at 20 degrees C depending on the coordination sites of the dmap ligands in 4a.

Journal Article↗
PubMed2006

Synthesis, characterization and luminescence property of N,N'-di(pyridine N-oxide-2-yl)pyridine-2,6-dicarboxamide and corresponding lanthanide (III) complexes.

A new ligand, N,N'-di(pyridine N-oxide-2-yl)pyridine-2,6-dicarboxamide (LH2) and its several lanthanide (III) complexes (La, Eu, Gd, Tb, Y) were synthesized and characterized in detail based on elemental analysis, conductivity measurements, IR, 1H NMR, MS (FAB) and UV spectra and TG-DTA studies. The results indicated that the composition of these binary complexes is [Ln(LH2)(NO3)2.H2O]NO3.nH2O (n=0-1); while the ligand has a good planar structure with strong hydrogen bonds. The fluorescence spectra exhibits that the Tb (III) complex and the Eu (III) complex display characteristic metal-centered fluorescence in solid state while ligand fluorescence is completely quenched. However, the Tb (III) complex displays more effective luminescence than the Eu (III) complex, which is attributed to especial effectivity in transferring energy from the lowest triplet energy level of the ligands (T) onto the excited state (5D4) of Tb (III) than that (5D1) of Eu (III).

Amides↗
PubMed1997

Reduction of intracellular pH by inhibitors of natural killer cell activity, nicardipine, methyl 2-(N-benzyl-N-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[1, 5-a]pyridine-3-yl)-1,4-dihydro-pyridine-3,5-dicarboxylate (AHC-52), and 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS).

Our previous study showed that nicardipine and its structural analog, methyl 2-(N-benzyl-N-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[1,5 -a]pyridine-3-yl)-1,4-dihydro-pyridine-3,5-dicarboxylate (AHC-52), which is devoid of calcium channel blocking activity, were equally effective in inhibiting natural killer (NK) cell activity, perhaps through inhibition of P-glycoprotein. In this study, we confirmed this finding using a human NK-like cell line, YTN, which is highly cytotoxic to JY cells. The YTN cell-mediated cytotoxicity toward JY cells was inhibited by nicardipine and AHC-52 in a concentration-dependent manner, the concentrations required for 50% inhibition being 14 and 7 microM, respectively. We then examined by flow cytometry whether these reagents modulate the intracellular pH (pHi), since P-glycoprotein reportedly plays a role in pHi homeostasis, perhaps by altering chloride translocation. Both reagents reduced pHi at concentrations similar to those required for inhibition of the cytotoxicity. In addition, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS), an inhibitor of anion exchangers, also inhibited NK cell activity, with an IC50 value of 160 microM, and reduced pHi at a similar concentration, although it is not a P-glycoprotein blocker. Thus, the inhibitory activities of nicardipine, AHC-52, and DIDS toward NK cell activity paralleled their lowering activities of pHi, suggesting the possibility that disregulation of pHi is related to inhibition of NK cell activity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Synthesis, crystal structure, spectral properties and cytotoxic activity of platinum(II) complexes of 2-acetyl pyridine and pyridine-2-carbaldehyde N(4)-ethyl-thiosemicarbazones.

The reactions of Na2PtCl4 with pyridine-2-carbaldehyde and 2-acetyl pyridine N(4)-ethyl-thiosemicarbazones, HFo4Et and HAc4Et respectively, afforded the complexes [Pt(Fo4Et)Cl], [Pt(HFo4Et)2]Cl2, [Pt(Fo4Et)2] and [Pt(Ac4Et)Cl], [Pt(HAc4Et)2]Cl2 x 2H2O, [Pt(Ac4Et)2]. The new complexes have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(Ac4Et)Cl] has been solved. The anion of Ac4E coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Intermolecular hydrogen, non-hydrogen bonds, pi-pi and weak Pt-pi contacts lead to aggregation and a supramolecular assembly. The cytotoxic activity for the platinum(II) complexes in comparison to that of cisplatin and thiosemicarbazones was evaluated in a pair of cisplatin-sensitive and -resistant ovarian cancer cell lines A2780 and A2780/Cp8. The platinum(II) complexes showed a cytotoxic potency in a very low micromolar range and were found able to overcome the cisplatin resistance of A2780/Cp8 cells.

Cell Division↗
PubMed2005

Structure and reactivity of a pyridine-1-imido-2-thiolato complex of iridium(III), CpIr(1-N-2-Spy), generated by photolysis of the (azido)(pyridine-2-thiolato) complex, CpIr(2-Spy)(N3).

Photolysis of the (azido)(pyridine-2-thiolato)iridium(III) complex CpIr(2-Spy)(N3) (1) gave a pyridine-1-imido-2-thiolato complex, CpIr(1-N-2-Spy) (2), in which one of the nitrogen atoms of the azide ligand has been inserted into the Ir-N(py) bond (Cp = eta5-C5Me5). Complex 2 reacted quantitatively with methyl iodide to give the N-methylated product, [CpIr(1-NMe-2-Spy)]I (3). X-ray crystallography revealed that both 2 and 3 have similar two-legged piano stool structures with planar 1-N-2-Spy2- or 1-NMe-2-Spy- ligands, which form iridacyclopentadienyl-like rings by moderate S(ppi)/N(ppi) to Ir(dpi) pi donation.

Journal Article↗
PubMed2006

Synthesis and lanthanide coordination properties of new 2,6-bis(N-tert-butylacetamide)pyridine and 2,6-bis(N-tert-butylacetamide)pyridine-N-oxide ligands.

The compound 2,6-bis(N-tert-butylacetamide)pyridine (2) was obtained via a Ritter synthesis, and oxidation with oxone provided the title pyridine-N-oxide (3). The compounds were characterized by spectroscopic methods, and the molecular structure of the N-oxide was determined by single-crystal X-ray diffraction methods. The coordination chemistry with Eu(NO3)3 was examined by using 1:1 and 2:1 ligand/Eu ratios, and a single-crystal X-ray analysis for Eu(3)(NO3)3(H2O) was completed. The ligand 3 is found to chelate in a tridentate fashion on the Eu(III).

Journal Article↗
PubMed2005

Pyridine N-alkylation by lithium, magnesium, and zinc alkyl reagents: synthetic, structural, and mechanistic studies on the bis(imino)pyridine system.

The 2,6-bis(alpha-iminoalkyl)pyridines 2,6-[ArNC(CR(3))](2)C(5)H(3)N [R = H, D; Ar = 2,6-i-Pr(2)C(6)H(3) (DIPP), 2,6-Me(2)C(6)H(3) (DMP)] react with MeLi in Et(2)O to give a binary mixture of products: the pyridine N-methylated species 2,6-[ArNC(CR(3))](2)C(5)H(3)N(Me)Li(OEt(2)) and the deprotonated/dedeuterated species 2-[ArNC(CR(3))],6-[ArNC(=CR(2))]C(5)H(3)NLi(OEt(2)). For R = D, the product ratio is 2:1 in favor of the N-methylated product, while, for R = H, the deprotonated product is favored by 5:1, increasing to 8:1 in toluene solvent. Warming solutions of the N-methylated species leads to clean conversion to the thermodynamically preferred deprotonated species. Crossover experiments show that MeLi is re-formed and dissociates from the terdentate ligand before deprotonating the ketimine methyl unit. For MgR(2) (R = Et, i-Pr) and ZnR(2) (R = Et) reagents, N-alkylation products are formed exclusively, but derivatives containing bulky aryl substituents are found to undergo further rearrangement to 2-alkylated species, arising by migration of the alkyl group of the N-alkyl moiety to the adjacent ring carbon atom. The reversibility of the N-alkylation process has been probed using deuterio-labeled Mg alkyl reagents and mixed alkyl zinc species. A cationic zinc derivative is shown to undergo "reverse" alkyl migration, from the heterocycle nitrogen atom to the zinc center. EPR spectroscopy reveals a paramagnetic intermediate in which the unpaired electron is delocalized over the heterocycle and di-imine moieties of the ligand, indicating that the N-alkylation reactions proceed via single electron-transfer processes.

Journal Article↗