- New benzimidazolium N-heterocyclic carbene precursors and their related Pd-NHC complex PEPPSI-type: Synthesis, structures, DFT calculations, biological activity, docking study, and catalytic application in the direct arylation
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New benzhydryl-5,6-dimethyl-(3-methylbenzyl)benzimidazolium salt as N-heterocyclic carbene precursors and their related new Pd-NHC complex PEPPSI-type with the general formula [PdBr2(NHC)(pyridine)] were prepared and theoretically studied. Quan
- ?zdemir, ?smail,?zdemir, Nam?k,Bensouici, Chawki,Benzerka, Saida,Boulebd, Houssem,Gürbüz, Nevin,Khiri-Meribout, Naima,Sandeli, Abd El-Krim
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- Synthesis, structures, DFT calculations, and catalytic application in the direct arylation of five-membered heteroarenes with aryl bromides of novel palladium-N-heterocyclic carbene PEPPSI-type complexes
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A new series of Pd-catalysts based on an N-heterocyclic carbene PEPPSI-type ligand (PEPPSI = pyridine enhanced precatalyst preparation stabilization and initiation) with the general formula [Pd(ii)Br2(NHC)(pyridine)] was synthesized and fully characterize
- ?zdemir, ?smail,?zdemir, Nam?k,Benzerka, Saida,Boulebd, Houssem,Gürbüz, Nevin,Khiri-Meribout, Naima,el-Krim Sandeli, Abd
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p. 17878 - 17892
(2021/10/12)
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- Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties
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A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.
- Staroń, Jakub,Kurczab, Rafa?,Warszycki, Dawid,Sata?a, Grzegorz,Krawczyk, Martyna,Bugno, Ryszard,Lenda, Tomasz,Popik, Piotr,Hogendorf, Adam S.,Hogendorf, Agata,Dubiel, Krzysztof,Mat?oka, Miko?aj,Moszczyński-P?tkowski, Rafa?,Pieczykolan, Jerzy,Wieczorek, Maciej,Zajdel, Pawe?,Bojarski, Andrzej J.
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supporting information
(2019/11/28)
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- Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies
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The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
- Ye, Jiqing,Yang, Xiao,Xu, Min,Chan, Paul Kay-sheung,Ma, Cong
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supporting information
(2019/09/06)
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- Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues
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Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba2+ current through Cav1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.
- Vallone, Alessandra,D'Alessandro, Sarah,Brogi, Simone,Brindisi, Margherita,Chemi, Giulia,Alfano, Gloria,Lamponi, Stefania,Lee, Soon Goo,Jez, Joseph M.,Koolen, Karin J.M.,Dechering, Koen J.,Saponara, Simona,Fusi, Fabio,Gorelli, Beatrice,Taramelli, Donatella,Parapini, Silvia,Caldelari, Reto,Campiani, Giuseppe,Gemma, Sandra,Butini, Stefania
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p. 698 - 718
(2018/03/24)
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- Access to Densely Functionalized Chalcone Derivatives with a 2-Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan-Yne Cyclization of N -(2-Furanylmethyl) Alkynamides under Air
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A protocol for synthesis of chalcone derivatives with a 2-pyridone subunit from N-(2-furanylmethyl) alkynamides is reported. This synthesis involves Pd/Cu-catalyzed oxidative furan-yne cyclization at room temperature in air and may proceed via nucleopalladation of the alkyne to form a vinylpalladium intermediate, with a furan ring acting as the nucleophile.
- Yang, Yongjie,Fei, ChengCheng,Wang, Kai,Liu, Bo,Jiang, Dingxin,Yin, Biaolin
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supporting information
p. 2273 - 2277
(2018/04/30)
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- 5-Aryl-2-furaldehydes in the synthesis of tetrahydropyrimidinones by Biginelli reaction
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5-Aryl-2-furaldehydes, obtained by furfural arylation with arenediazonium salts, react with ethyl acetoacetate or acetylacetone and (thio)- urea in the presence of FeCl3·6H2O as a catalyst. A series of ethyl 4-(5-aryl-2-furyl)-6-methyl-2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine- 5-carboxylates was obtained.
- Vakhula, Andriy R.,Horak, Yuriy I.,Lytvyn, Roman Z.,Lesyuk, Alexandra I.,Kinzhybalo, Vasyl,Zubkov, Fedor I.,Obushak, Mykola D.
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p. 545 - 549
(2018/07/05)
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- Discovery of selective protein arginine methyltransferase 5 inhibitors and biological evaluations
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Protein arginine methyltransferase 5 (PRMT5) is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure–activity relationship studies were carried out to discover novel PRMT5i, which finally led to the identification of a number of new PRMT5i. The most active compound, P5i-6, exhibited a considerable inhibitory potency against PRMT5 with an IC50 value of 0.57?μm, and a high selectivity for PRMT5 against other tested PRMTs. It displayed a very good antiviability activity against two colorectal cancer cell lines, HT-29 and DLD-1, and one hepatic cancer cell line, HepG2, in a sensitivity assay against 36 different cancer cell lines. Western blot assays indicated that P5i-6 selectively inhibited the symmetric dimethylations of H4R3 and H3R8 in DLD-1 cells. Overall, P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents.
- Ji, Sen,Ma, Shuang,Wang, Wen-Jing,Huang, Shen-Zhen,Wang, Tian-Qi,Xiang, Rong,Hu, Yi-Guo,Chen, Qiang,Li, Lin-Li,Yang, Sheng-Yong
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p. 585 - 598
(2017/04/06)
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- Novel inhibitors of Plasmodium falciparum based on 2,5-disubstituted furans
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Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N1-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N3,N3-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC50= 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
- Krake, Susann H.,Martinez, Pablo David G.,McLaren, Jenna,Ryan, Eileen,Chen, Gong,White, Karen,Charman, Susan A.,Campbell, Simon,Willis, Paul,Dias, Luiz Carlos
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supporting information
p. 929 - 936
(2016/12/23)
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- Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation
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Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated Bact complexes. Characterization of the stalled complexes (designated B028) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other Bact complex proteins. The U2/U6 RNA network in B028 complexes differs from that of the Bact complex, consistent with the idea that the catalytic RNA core forms stepwise during the B to Bact transition and is likely stabilized by the Prp19/CDC5L complex and related proteins. Taken together, our data provide new insights into the RNP rearrangements and extensive exchange of proteins that occurs during spliceosome activation.
- Sidarovich, Anzhalika,Will, Cindy L.,Anokhina, Maria M.,Ceballos, Javier,Sievers, Sonja,Agafonov, Dmitry E.,Samatov, Timur,Bao, Penghui,Kastner, Berthold,Urlaub, Henning,Waldmann, Herbert,Lührmann, Reinhard
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- Antibacterial and antifungal properties of guanylhydrazones
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A series of novel guanylhydrazones were designed, synthesized and characterized. All the compounds were screened for their antibacterial and antifungal activity. Compounds 26 and 27 showed excellent antibacterial activities against Staphylococcus aureus A
- Ajda?i?, Vladimir,Lazi?, Jelena,Moji?evi?, Marija,?egan, Sandra,Nikodinovic-Runic, Jasmina,Opsenica, Igor M.
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p. 641 - 649
(2017/08/09)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
-
- Design and synthesis of natural product derivatives with selective and improved cytotoxicity based on a sesquiterpene scaffold
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Brasilamide E (1) is a bisabolane sesquiterpenoid isolated from the solid-substrate fermentation cultures of a plant endophytic fungus Paraconiothyrium brasiliense. The compound specifically inhibited proliferation of the MCF-7 cells, but did not show cyt
- Zhang, Yang,Zhang, Zhuowei,Wang, Bo,Liu, Ling,Che, Yongsheng
-
supporting information
p. 1885 - 1888
(2016/04/05)
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- Mono- and biscouplings using triarylbismuths for the atom-efficient arylations of functionalized furans under palladium catalysis
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Palladium-catalyzed cross-coupling reactions of functionalized bromofurans with triarylbismuths have been described for the atom-economic synthesis of functionalized arylfuran systems. The coupling reactions using triarylbismuths with various 2-bromofurans and 2,5-dibromofuran underwent smoothly to afford the corresponding 2-arylfurans and 2,5-diarylfurans in high yields in a short reaction time (one hour). Georg Thieme Verlag Stuttgart · New York.
- Rao, Maddali L. N.,Awasthi, Dheeraj K.,Talode, Jalindar B.
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supporting information; experimental part
p. 1907 - 1912
(2012/09/22)
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- CYCLIC CARBOXYLIC ACID RHODANINE DERIVATIVES FOR THE TREATMENT AND PREVENTION OF TUBERCULOSIS
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Disclosed are methods for the prevention or treatment of tuberculosis in a subject infected with Mycobacterium tuberculosis by administering rhodanine derivatives of formula (I), as well as some novel such compounds. Other embodiments are also disclosed.
- -
-
Page/Page column 9
(2010/08/22)
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- New class of potent antitumor acylhydrazone derivatives containing furan
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A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited excellent activity against the selected cancer cell lines. In particular, IIf (IC50 = 16.4 μM) was better than doxorubicin (IC50 = 53.3 μM) against human promyelocytic leukemic cells (HL-60). Their toxicities were predicted in silico. The results showed that compounds II were safe and eligible to be development candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.
- Cui, Zining,Li, Ying,Ling, Yun,Huang, Juan,Cui, Jingrong,Wang, Ruiqing,Yang, Xinling
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scheme or table
p. 5576 - 5584
(2011/02/22)
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- Synthesis and fungicidal activity of aryl carbamic acid-5-aryl-2- furanmethyl ester
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Chitin, a major structural component of insect cuticle and fungus cell wall but absent in plants and vertebrates, is regarded as a safe and selective target for pest control agents. Chitin synthesis inhibitors (CSIs) have been well-known as insect growth regulators (IGRs) but rarely found as fungicides in agriculture. To find novel CSIs with good activity, benzoylphenylurea, a typical kind of CSIs, was chosen as the lead compound and 26 novel aryl carbamic acid-5-aryl-2-furanmethyl esters were designed by converting the urea linkages of benzoylphenylureas to carbamic acid esters and changing the aniline parts into furanmethyl groups. The title compounds were synthesized and their structures confirmed by IR, 1H NMR, and elemental analysis. Preliminary insecticidal and fungicidal bioassays were carried out. The results indicated that the title compounds had no insecticidal effect on Culex pipiens pallens and Plutella xylostella Linnaeus, but most compounds exhibited good fungicidal activities against Corynespora cassiicola, Thanatephorus cucumeris, Botrytis cinerea, and Fusarium oxysporum. In particular, compounds V-4, V-6, V-7, and V-8 showed better activities against the four strains than those of the commercialized fungicides. The morphologic result suggested that compound V-21 had disturbed the cell wall formation of C. cassiicola. The results indicated that modification on the urea linkage of benzoylphenylurea was an effective way to discover new candidates for fungicides.
- Ying,Bao-Ju,Ling,Miao, Hong-Jian,Yan-Xia,Yang, Xin-Ling
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scheme or table
p. 3037 - 3042
(2011/07/31)
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- Low catalyst loading ligand-free palladium-catalyzed direct arylation of furans: An economically and environmentally attractive access to 5-arylfurans
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The direct 5-arylation of furans at very low catalyst loading using Pd(OAc)2 as catalyst without added ligand proceed in high yields. Turnover numbers up to 10000 have been obtained for the coupling of several activated aryl bromides. A wide ra
- Dong, Jia Jia,Roger, Julien,Pogan, Franc,Doucet, Henri
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experimental part
p. 1832 - 1846
(2011/03/18)
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- Synthesis of fluorescent enone derived α-amino acids
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The development of a facile and general method for the preparation of enone derived α-amino acids is described. The key step involves a Horner-Wadsworth-Emmons reaction between an aspartic acid derived β-keto phosphonate ester and a range of aldehydes resulting in the formation of highly functionalised α-amino acids in good yields. An efficient two-stage deprotection process using mild conditions was developed to give the parent α-amino acids. Application of this methodology has produced a novel fluorescent α-amino acid that has potential as a biological marker.
- Fowler, Lindsay S.,Ellis, David,Sutherland, Andrew
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supporting information; experimental part
p. 4309 - 4316
(2009/12/06)
-
- Inhibitors of HCV NS5B polymerase. Part 1: Evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid
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A novel series of nonnucleoside HCV NS5B polymerase inhibitors were prepared from (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid, a high throughput screening lead. SAR studies combined with structure based drug design focusing on the southern heterobiaryl region of the template led to the synthesis of several potent and orally bioavailable lead compounds. X-ray crystallography studies were also performed to understand the interaction of these inhibitors with HCV NS5B polymerase.
- Pfefferkorn, Jeffrey A.,Greene, Meredith L.,Nugent, Richard A.,Gross, Rebecca J.,Mitchell, Mark A.,Finzel, Barry C.,Harris, Melissa S.,Wells, Peter A.,Shelly, John A.,Anstadt, Robert A.,Kilkuskie, Robert E.,Kopta, Laurice A.,Schwende, Francis J.
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p. 2481 - 2486
(2007/10/03)
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- Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-3- benzoylphenyl)-3-arylfurylacrylic acid amides
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We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range. We have designed arylfurylacryl-
- Mitsch, Andreas,Wi?ner, Pia,Silber, Katrin,Haebel, Peter,Sattler, Isabel,Klebe, Gerhard,Schlitzer, Martin
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p. 4585 - 4600
(2007/10/03)
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- Dantrolene analogues revisited: General synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle
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The general synthesis of dantrolene analogues with various substituents on its phenyl ring has been developed via palladium-catalyzed cross-coupling reactions, the Stille or Suzuki reaction, as the key step. The effects of synthesized analogues have been evaluated by two kinds of Ca2+ release modes from sarcoplasmic reticulum (SR) of mouse skeletal muscle fibers based on: (1) the measurement of twitch contraction caused by the physiological Ca2+ release (PCR) of intact skeletal muscle and (2) the rate of Ca2+-induced Ca2+ release (CICR) in saponin-treated skinned muscle fibers. Although dantrolene, a lead compound, inhibits both twitch contraction and CICR, some structurally modified analogues exhibit one or the other of these effects. The methoxy congener, GIF-0185, potently inhibits the twitch contraction without affecting the CICR, while GIF-0166 and GIF-0248, the ortho-nitro regioisomer and ortho, ortho-dinitro substituted analogues, respectively, doubly potentiate the CICR exclusively.
- Hosoya, Takamitsu,Aoyama, Hiroshi,Ikemoto, Takaaki,Kihara, Yasutaka,Hiramatsu, Toshiyuki,Endo, Makoto,Suzuki, Masaaki
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p. 663 - 673
(2007/10/03)
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- Efficient coupling of heteroaryl halides with arylboronic acids in the presence of a palladium-tetraphosphine catalyst
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Cis, cis, cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclopentane: ·1/2[PdCl(C3H5)]2 system catalyses the Suzuki cross-coupling of heteroaryl halides with a range of arylboronic acids with very high ratio substrate/catalyst in good yields. Substrates such as pyridines, quinolines, thiophenes, an indole, pyrimidines or a furane have been used successfully.
- Feuerstein, Marie,Doucet, Henri,Santelli, Maurice
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p. 327 - 336
(2007/10/03)
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- Structure-activity relationships of novel anti-malarial agents. Part 4: N-(3-Benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides
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In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties.
- Wiesner, Jochen,Mitsch, Andreas,Wissner, Pia,Kraemer, Oliver,Jomaa, Hassan,Schlitzer, Martin
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p. 2681 - 2683
(2007/10/03)
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- Efficient coupling of heteroaryl bromides with arylboronic acids in the presence of a palladium-tetraphosphine catalyst
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The cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C 3H5)]2 system catalyses the Suzuki cross-coupling of heteroaryl bromides with arylboronic acids with a very high substrate/catalyst ratio in good yields. Substrates such as pyridines, quinolines, thiophenes, an indole, a pyrimidine or a furane have been used successfully.
- Feuerstein, Marie,Doucet, Henri,Santelli, Maurice
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p. 5659 - 5662
(2007/10/03)
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- (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]- N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor
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Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5- lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N- hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]- N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene- mediated disorders.
- Brooks,Stewart,Basha,Bhatia,Ratajczyk,Martin,Craig,Kolasa,Bouska,Lanni,Harris,Malo,Carter,Bell
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p. 4768 - 4775
(2007/10/03)
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- 5-Phenyl-2-furamidines: A new chemical class of potential antidepressants
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A series of 5-phenyl-2-furamidines has been synthesized and evaluated for antidepressant activities. Substitution in the phenyl ring with a nitro (4) or an amino (12) group in the ortho-position resulted in an increase in antidepressant activity. Both 4 and 12 antagonized tetrabenazine-induced ptosis in rodents and inhibited norepinephrine (noradrenaline) uptake into crude synaptosomes of whole mouse brain at doses or concentrations comparable to those of the tricyclic antidepressants. However, these compounds did not possess the anticholinergic and antihistaminic activities common to tricyclic antidepressants. In addition, they lacked monoamine oxidase inhibitory activity. The 5-phenyl-2-furamidines represent a new chemical class of antidepressants and may be useful for depressive patients who cannot tolerate the compromising side effects of the tricyclic antidepressants and monoamine oxidase inhibitors.
- Pong,Pelosi Jr.,Wessels,Yu,Burns,White,Anthony Jr.,Ellis,Wright,White Jr.
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p. 1411 - 1416
(2007/10/02)
-