- Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation
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In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
- Relitti, Nicola,Saraswati, A. Prasanth,Chemi, Giulia,Brindisi, Margherita,Brogi, Simone,Herp, Daniel,Schmidtkunz, Karin,Saccoccia, Fulvio,Ruberti, Giovina,Ulivieri, Cristina,Vanni, Francesca,Sarno, Federica,Altucci, Lucia,Lamponi, Stefania,Jung, Manfred,Gemma, Sandra,Butini, Stefania,Campiani, Giuseppe
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- Synthesis and Biological Evaluation of Fentanyl Analogues Modified at Phenyl Groups with Alkyls
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A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce β-arrestin2 recruitment. Compound 12 is a potent μ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak β-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak β-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.
- Qin, Yajuan,Ni, Luofan,Shi, Jiawei,Zhu, Zhiying,Shi, Saijian,Lam, Ai-Leen,Magiera, Julia,Sekar, Sunderajhan,Kuo, Andy,Smith, Maree T.,Li, Tingyou
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p. 201 - 208
(2018/09/25)
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- Metabolism of butyrylfentanyl in fresh human hepatocytes: Chemical synthesis of authentic metabolite standards for definitive identification
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The metabolism of butyrylfentanyl, a new designer drug, was investigated using fresh human hepatocytes isolated from a liver-humanized mouse model. In the culture medium of hepatocytes incubated with butyrylfentanyl, the desphenethylated metabolite (nor-butyrylfentanyl), w-hydroxy-butyrylfentanyl, (w-1)-hydroxy-butyrylfentanyl, 4′-hydroxy-butyrylfentanyl, β-hydroxy-butyrylfentanyl, 4′-hydroxy-3′- methoxy-butyrylfentanyl, and w-carboxy-fentanyl were identified as the metabolites of butyrylfentanyl. Each metabolite was definitively identified by comparing the analytical data with those of authentic standards. The amount of the main metabolite, nor-butyrylfentanyl, reached 37% of the initial amount of butyrylfentanyl at 48 h. W-Hydroxy-butyrylfentanyl and (w-1)-hydroxy-butyrylfentanyl, formed by hydroxylation at the Nbutyryl group of butyrylfentanyl, were the second and third largest metabolites, respectively. The majority of 4′-hydroxy-butyrylfentanyl and 4′-hydroxy-3′-methoxy-butyrylfentanyl was considered to be conjugated. CYP reaction phenotyping for butyrylfentanyl using human liver microsomes and various anti-CYP antibodies revealed that CYP3A4 was involved in the formation of nor-butyrylfentanyl, (w-1)-hydroxybutyrylfentanyl, and β-hydroxy-butyrylfentanyl. In contrast, CYP2D6 was involved in the formation of w-hydroxy-butyrylfentanyl.
- Kanamori, Tatsuyuki,Iwata, Yuko Togawa,Segawa, Hiroki,Yamamuro, Tadashi,Kuwayama, Kenji,Tsujikawa, Kenji,Inoue, Hiroyuki
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p. 623 - 630
(2019/05/08)
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- Preparation of Fentanyl Labeled with Carbon-14
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A convenient synthetic pathway for 14C labeling of fentanyl [N-(1-phenethyl-4-piperidinyl)- propionanilide], a widely used narcotic analgesic agent, with good radiochemical yield was developed.
- Nami,Dabiri,Shirvani,Ahmadi Faghih,Javaheri
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are heterocyclyl compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
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Paragraph 00238; 00291
(2014/07/21)
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- Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl) propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice
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Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a popular narcotic analgesic agent that is clinically used worldwide. However, fentanyl and its several analogs have caused abuse and fatalities in humans due to overdosing and narrow therapeutic index. The present study reports the synthesis and comparative bioefficacy of fentanyl and its four analogs, viz., N-(1-propyl-4-piperidinyl)propionanilide (1), N-(1-(2-phenoxyethyl)-4- piperidinyl)propionanilide (2), N-(1-(3-phenoxypropyl)-4-piperidinyl) propionanilide (3) and N-(1-(2-cyanoethyl)-4-piperidinyl)propionanilide (4), where the phenethyl chain of fentanyl was replaced by different functional groups, viz., alkyl, ethereal, and nitrile moieties. The median lethal dose (LD50) of the compounds was determined by three different routes and all the analogs were found to be safer than fentanyl. Observational assessment on spontaneous activities of the central nervous system, peripheral nervous system, and autonomic nervous system revealed that all the analogs were similar to fentanyl. Further, the neurotoxic effects of all the analogs were reversed by naloxone hydrochloride (opioid antagonist), confirming that their effects were mediated through opioid receptors. Antinociceptive activity was displayed by all the compounds and their median effective dose (ED50) and analgesic potency ratio were more or less similar to fentanyl. The lowest ED50 (23.7) and the highest potency ratio (1.18) was observed in the case of 2. However, the maximum therapeutic index was afforded by 4. The study indicates the promising role of some new opioid analgesics.
- Gupta, Pradeep Kumar,Yadav, Shiv Kumar,Bhutia, Yangchen Doma,Singh, Poonam,Rao, Pooja,Gujar, Niranjan Laxman,Ganesan, Kumaran,Bhattacharya, Rahul
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p. 3888 - 3896
(2013/07/26)
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- Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain
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Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.
- Vardanyan, Ruben,Vijay, Gokhale,Nichol, Gary S.,Liu, Lu,Kumarasinghe, Isuru,Davis, Peg,Vanderah, Todd,Porreca, Frank,Lai, Josephine,Hruby, Victor J.
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experimental part
p. 5044 - 5053
(2009/12/04)
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- Understanding the structural requirements of 4-anilidopiperidine analogues for biological activities at μ and δ opioid receptors
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New 4-anilidopiperidine analogues in which the phenethyl group of fentanyl was replaced by several aromatic ring-contained amino acids (or acids) were synthesized to study the biological effect of the substituents on μ and δ opioid receptor interactions. These analogues showed broad (47 nM-76 μM) but selective (up to 17-fold) binding affinities at the μ opioid receptor over the δ opioid receptor, as predicted from the message-address concept.
- Lee, Yeon Sun,Nyberg, Joel,Moye, Sharif,Agnes, Richard S.,Davis, Peg,Ma, Shou-wu,Lai, Josephine,Porreca, Frank,Vardanyan, Ruben,Hruby, Victor J.
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p. 2161 - 2165
(2008/02/01)
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- 4- ARYL(PIPERIDIN-4-YL)] AMINOBENZAMIDES WHICH BIND TO THE DELTA-OPIOID RECEPTOR
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4-[aryl(piperidin-4-yl)] aminobenzamides are delta-opioid receptor agonists/antagonists of formula (I). As delta-opioid receptor agonists, such compounds are useful as analgesics. Depending on their agonist/antagonist effect, such compounds may also be useful immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases. In formula (I), [Ar is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 1 to 3 R; R - R are described in the application].
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Page/Page column 16-17
(2008/06/13)
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- AGONIST AND ANTAGONIST LIGANDS OF THE NOCICEPTIN RECEPTOR
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Novel piperidyl indolinone compounds are provided that are useful as agonist and antagonist ligands of the nociceptin receptor. The compounds are useful to treat a variety of disorders, and are particularly useful as analgesics.
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Page/Page column 33
(2008/06/13)
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- RECEPTOR REGULATOR
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A compound having a partial structure represented by the formula (A) (wherein ring Xa represents a nitrogen-containing ring and R represents optionally substituted amino) or a salt thereof. The compound or salt is highly effective in regulating neuromedin U receptors and is useful as a preventive/therapeutic agent for hypertension, etc.
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Page/Page column 32
(2010/02/13)
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- A new series of M3 muscarinic antagonists based on the 4-amino-piperidine scaffold
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A series of 4-amino-piperidine containing molecules have been synthesized and structure-affinity relationship toward the M3-muscarinic receptor has been investigated. Chemical modulations provided molecules with Ki for the human M3-R up to 1 nM with variable selectivity (3- to 40-fold) over the human M2-R. Compounds 2 (pA2=8.3, 8.6) demonstrates in vitro on guinea pig bladder and ileal strips potent anticholinergic properties and tissue selectivity.
- Diouf,Gadeau,Chelle,Gelbcke,Talaga,Christophe,Gillard,Massingham,Guyaux
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p. 2535 - 2539
(2007/10/03)
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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- Carbon-13 nuclear magnetic resonance spectra of fentanyl analogs
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Natural abundance carbon-13 chemical shifts are reported for the hydrochloride salts of fentanyl and fifteen analogs. The signals are assigned on the basis of chemical shift theory, SFORD multiplicities, signal intensities, comparisons with model compounds, and thiophene carbon-proton coupling constants. In addition to its forensic value, the data suggest that the solution conformations of the analogs are similar to that of fentanyl hydrochloride.
- Brine,Boldt,Huang,Sawyer,Carroll
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p. 677 - 686
(2007/10/02)
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- Aminohaloborane in Organic Synthesis. IX. Exclusive ortho Acylation Reaction of N-Monoaminoalkylanilines
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The exclusive ortho acylation reaction of aniline derivatives using boron trichloride made possible the one-step synthesis of 2-acyl-N-monoaminoalkylanilines (1) and the corresponding imines (2) from N-monoaminoalkylanilines, even in the case of compounds with a bulky substituent at the nitrogen atom.Conventional methods only give 1 via elaborate procedures.Keywords: regioselective reaction; 2-acylaniline derivative; 2-acylaniline-imine derivative; boron trichloride
- Adachi, Makoto,Sasakura, Kazuyuki,Sugasawa, Tsutomu
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p. 1826 - 1835
(2007/10/02)
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