[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist

A series of new piperidinomethylphenoxypropylamine‐type histamine H₂ receptor (H₂R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N‐[6‐(3,4‐dioxo‐2‐{3‐[3‐(piperidin‐1‐ylmethyl)phenoxy]propylamino}cyclobut‐1‐enylamino)hexyl]‐(2,3‐³H₂)propionic amide ([³H]UR‐DE257) was performed. The radioligand (specific activity: 63 Ci mmol^?1) had high affinity for human, rat, and guinea pig H₂R (hH₂R, Sf9 cells: K_d, saturation binding: 31 nM , kinetic studies: 20 nM ). UR‐DE257 revealed high H₂R selectivity on membranes of Sf9 cells, expressing the respective hH_xR subtype (K_i values: hH₁R: >10 000 nM , hH₂R: 28 nM , hH₃R: 3800 nM , hH₄R: >10 000 nM ). In spite of insurmountable antagonism, probably due to rebinding of [³H]UR‐DE257 to the H₂R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H₂R affinities in competition binding assays.     

Heme Oxygenase Inhibition by 1‐Aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and Their Derivatives

Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC₅₀<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.     

Chemistry and Pharmacology of Nicotinic Ligands Based on 6‐[5‐(Azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol (AMOP‐H‐OH) for Possible Use in Depression

AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)₃(β2)₂‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.     

(2,2‐Diphenyl‐[1,3]oxathiolan‐5‐ylmethyl)‐(3‐phenyl‐propyl)‐amine: a Potent and Selective 5‐HT1A Receptor Agonist

A selective 5‐HT _1A receptor agonist : A new series of ligands acting at 5‐HT_1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pK_i=8.72, pD₂=7.67, E_max=85) and selectivity (5‐HT_1A/α_1D>150), and represents a new 5‐HT_1A agonist chemotype.

     

Derivation of a Retinoid X Receptor Scaffold from Peroxisome Proliferator‐Activated Receptor γ Ligand 1‐Di(1H‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene

PPARγ agonist DIM‐Ph‐4‐CF ₃ , a template for RXRα agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF₃ is reported to inhibit cancer growth independent of PPARγ and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARγ ligands activate RXR, DIM‐Ph‐4‐CF₃ was investigated as an RXR ligand. It displaces 9‐cis‐retinoic acid from RXRα but does not activate RXRα. Structure‐based direct design led to an RXRα agonist.

     

1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors

The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ^?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found.     

Energetic Salts of 5‐(5‐Azido‐1H‐1,2,4‐triazol‐3‐yl)tetrazole

Several metal and nitrogen‐rich salts of the recently presented 5‐(5‐azido‐1H‐1,2,4‐triazol‐3‐yl)tetrazole (AzTT), including silver ( 1 ), copper(I) ( 2 ), potassium ( 3 ), cesium ( 4 ), copper(II) ( 7 ), ammonium ( 8 ), and guanidinium ( 9 ), as well as the respective double‐salts of 3 , 4 , 8 and 9 , were prepared and well characterized by IR and multinuclear (¹H, ¹³C, ¹⁴N) NMR spectroscopy, DSC, mass spectrometry, elemental analysis and one ( 4 ) additionally by single‐crystal X‐ray diffraction. The sensitivities towards impact, friction and electrostatic discharge were determined according to BAM standards, revealing most of the metal salts as highly sensitive and the nitrogen‐rich salts as insensitive. The metal salts were further tested for their ability of being primary explosives.     

6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC₅₀=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development.     

Aminopalladation‐Triggered Carbene Insertion Reaction: Synthesis of 2‐(1H‐Indol‐3‐yl)acetates

The first example of a nucleopalladation‐triggered carbene insertion reaction for the synthesis of C‐3 alkylated indole derivatives from ortho‐alkynyltrifluoroacetanilides and α‐diazoacetates is presented; it involves a palladium catalyst and a weak base in the open air. Yields range from 49–88% with excellent functional group tolerance. The reaction proceeds through intramolecular aminopalladation of alkynes followed by carbene insertion. Migratory insertion of the carbene into the σ‐indolylpalladium intermediate was favored over N H insertion.

     

[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high‐affinity (IC₅₀ 2.1–12 nm ) indole‐5‐carboxylic acid‐based inhibitors of cPLA2α, namely 3‐isobutyryl‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 1 ); 3‐acetyl‐1‐(2‐oxo‐3‐(4‐(4‐(trifluoromethyl)phenoxy)phenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 2 ); 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 3 ); and 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(3‐(4‐octylphenoxy)‐2‐oxopropyl)‐1H‐indole‐5‐carboxylic acid ( 4 ), for labelling in carboxyl position with carbon‐11 (t_1/2=20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. Compounds [¹¹C] 1 – 4 were obtained for intravenous injection in adequate overall yields (1.1–5.5 %) from cyclotron‐produced [¹¹C]carbon dioxide and with moderate molar activities (70–141 GBq μmol^?1) through the use of Pd⁰‐mediated [¹¹C]carbon monoxide insertion on iodo precursors. Measured logD_7.4 values were within a narrow moderate range (1.9–2.4). After intravenous injection of [¹¹C] 1 – 4 in mice, radioactivity uptakes in brain peaked at low values (≤0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non‐radioactive ligands did not alter brain time–activity curves. Brain uptakes of radioactivity after administration of [¹¹C] 1 to wild‐type and P‐gp/BCRP dual knock‐out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [¹¹C] 1 and others in this structural class, are not substrates for efflux transporters.     

Polyamides obtained by direct polycondesation of 4‐[4‐[9‐[4‐(4‐aminophenoxy)‐3‐methyl‐phenyl] fluoren‐9‐YL]‐2‐methyl‐phenoxy]aniline with dicarboxylic acids based on a diphenyl‐silane moiety

Polyamides (PAs) containing fluorene, oxyether, and diphenyl‐silane moieties in the repeating unit were synthesized in > 85% yield by direct polycondesation between a diamine and four dicarboxylic acids. Alternatively, one PA was synthesized from an acid dichloride. The diamine 4‐[4‐[9‐[4‐(4‐aminophenoxy)‐3‐methyl‐phenyl]fluoren‐9‐yl]‐2‐methyl‐phenoxy]aniline ( 3 ) was obtained from the corresponding dinitro compound, which was synthesized by nucleophilic aromatic halogen displacement from p‐chloronitrobenzene and 9,9‐bis (4‐hydroxy‐3‐methyl‐phenyl)fluorene ( 1 ). Monomers and polymers were characterized by FTIR and ¹H, ¹³C, and ²⁹Si‐NMR spectroscopy and the results were in agreement with the proposed structures. PAs showed inherent viscosity values between 0.14 and 0.43 dL/g, indicative of low molecular weight species, probably of oligomeric nature. The glass transition temperature (T_g) values were observed in the 188–211°C range by DSC analysis. Thermal decomposition temperature (TDT_10%) values were above 400°C due to the presence of the aromatic rings in the diamine. All PAs showed good transparency in the visible region (>88% at 400 nm) due to the incorporation of the fluorene moiety. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Palladium‐Catalyzed Intramolecular Annulation of 3‐[2‐(2‐Iodobenzylamino)aryl]‐N‐arylpropiolamides: Synthesis of 3‐[5H‐Dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones

A novel palladium‐catalyzed intramolecular tandem annulation method is presented for the synthesis of 3‐[5H‐dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones. This method allows the conversion of various 3‐[2‐(2‐iodobenzylamino)aryl]‐N‐arylpropiolamides to the corresponding 3‐[5H‐dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones through the diarylation of an alkyne.     

Synthesis and characterization of α‐butyl‐omega‐{3‐[2‐hydroxy‐3‐(N‐methyl‐N‐hydroxy‐ ethylamino)propoxy]propyl}polydimethylsiloxane

A novel synthesis path for the monotelechelic polydimethylsiloxane with a diol‐end group, α‐butyl‐omega‐{3‐[2‐hydroxy‐3‐(N‐methyl‐N‐hydroxyethylamino)propoxy]propyl}polydimethylsiloxane, is described in this article. The preparation included three steps, which were anionic ring‐opening polymerization, hydrosilylation, and epoxy addition. The structure and polydispersity index of the products were analyzed and confirmed by FTIR, ¹H NMR, ¹³C NMR, H? H, and C? H. Correlated Spectroscopy and gel permeation chromatography. The results demonstrated that each step was successfully carried out and the targeted products were accessed in all cases. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

3‐Hydroxy‐2‐[1′‐phenyl‐3′‐(p‐chlorophenyl)‐4′‐pyrazolyl]‐4‐oxo‐4H‐1‐benzopyran as a spectrophotometric reagent for trace determination of tungsten(vi)

3‐Hydroxy‐2‐[1′‐phenyl‐3′‐(p‐chlorophenyl)‐4′‐pyrazolyl]‐4‐oxo‐4H‐1‐benzopyran solution in acetone forms a yellow‐coloured complex with tungsten(vi ) in perchloric acid medium which is extractable into chloroform after equilibration. In this study, tests were carried out on this compound and it was found to be quite stable and to obey Beer’s law. Interactions with various ions were studied and the molar absorptivity, Sandell’s sensitivity and relative standard deviation were also investigated. Job’s method, the mole ratio method and the equilibrium‐shift method were also used. The ratio of metal to ligand was measured using a method that was simpler, more accurate, sensitive, rapid and selective as compared with existing methods. This method is applicable to the analysis of various samples of varied composition.     

5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site

A series of bioisosteric N₁‐ and N₂‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABA_AR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC₅₀～300 μM ) is a weak antagonist at the α₁β₂γ₂ GABA_AR, whereas substituting the N₁‐ or N₂‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABA_ARs. Docking studies using a α₁β₂γ₂ GABA_AR homology model along with the obtained SAR indicate that the N₁‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N₂‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.     

Synthesis and characterization of poly(acrylic acid‐co‐N‐[3‐(dimethylamino)propyl]‐methacrylamide) hydrogel membranes for biomedical applications

A series of new hydrogel membranes with different compositions of acrylic acid (AAc) and N‐[3‐(dimethylamino)propyl]‐methacrylamide (DMAPMA) were prepared by aqueous copolymerization, without using chemical crosslinker or radiation. Chemical structure of the membranes (PADMAs) was characterized by Fourier transform infrared spectroscopy (FTIR). Swelling experiments were carried out in simulated body fluid (SBF) at 37 ± 1°C to investigate degree of swelling, dimensional stability, and pore size of the PADMA membranes. In SBF, the variation of pore size with membrane composition was monitored by optical microscopic technique. Morphology of the membranes was characterized, before and after exposure to SBF, by scanning electron microscopy (SEM). It was observed that the membranes are composed of closely packed nanogels of ～200 nm. Macroporous network structure of the SBF‐swollen PADMA was also observed to be composed of interconnected nanogels. Blood compatibility of the PADMA membranes was evaluated in vitro, by performing hemolysis assay and thrombogenicity assay. The extent of hemolysis due to PADMA membranes was found to be <2%, which ensured that all of the membranes were highly hemocompatible. Salicylic acid (SA) was chosen as a model drug. Diffusion coefficient of SA through PADMA membranes was investigated. It was observed that membrane composition regulates both pore size and drug diffusion. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Synthesis and characterization of poly{N‐[3‐(dimethylamino) propyl] methacrylamide‐co‐itaconic acid} hydrogels for drug delivery

A novel pH‐sensitive hydrogel system composed of itaconic acid (IA) and N‐[3‐(dimethylamino) propyl] methacrylamide was designed. This system was prepared by aqueous copolymerization with N,N‐methylene bisacrylamide as a chemical crosslinker. The chemical structure of the hydrogels was characterized by Fourier transform infrared (FTIR) spectroscopy. The microstructure and morphology of the hydrogels were evaluated by X‐ray diffraction (XRD) and scanning electron microscopy (SEM). The SEM study of hydrogels on higher magnification revealed a highly porous morphology with uniformly arranged pores ranging from 40 to 200 μm in size. XRD analysis revealed the amorphous nature of the hydrogels, and it was found that an increase in the IA content in the monomer feed greatly reduced the crystallinity of the hydrogels. Swelling experiments were carried out in buffer solutions at different pH values (1.2–10) at 37°C ± 1°C to investigate their pH‐dependent swelling behavior and dimensional stability. An increase in the acid part (IA) increased the swelling ratio of the hydrogels. Temperature‐sensitive swelling of the hydrogels was investigated at 20–70°C in simulated intestinal fluid. The hydrogels swelled at higher temperatures and shrank at lower temperatures. 5‐Aminosalicylic acid (5‐ASA) was selected as a model drug, and release experiments were carried out under simulated intestinal and gastric conditions. 5‐ASA release from the poly N‐[3‐(dimethylamino) propyl] methacrylamide‐co‐itaconic acid‐80 (PDMAPMAIA‐80) hydrogel was found to follow non‐Fickian diffusion mechanism under gastric conditions, and a super case II transport mechanism was found under intestinal conditions. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011