- Syntheses, biological evaluation, and molecular modeling of 18F-labeled 4-anilidopiperidines as μ-opioid receptor imaging agents
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The synthesis, evaluation, and molecular modeling of a series of 18F-labeled 4-anilidopiperidines with high affinities for the μ-opioid receptor (μ-OR) are reported. On the basis of the high brain uptake and selective retention in brain regions that contain a high concentration of the μ-OR, combined with a good metabolic stability, [ 18F]fluoro-pentyl carfentanil ([18F]4) and 2-(±)[18F]-fluoropropyl-sufentanil ([18F]6) were selected as the lead compounds for further evaluation. The binding affinity to the human μ-OR was 0.74 and 0.13 nM for [18F]4 and [ 18F]6, respectively. In vitro autoradiography of [18F] 4 and [18F] 6 on rat brain sections produced patterns in accordance with the known distribution of μ-OR expression. Structure-activity relationships of the fluorinated compounds are discussed with respect to the interaction with an activated-state model of the μ-OR. Taken together, the in vivo and in vitro data indicate that [18F] 4 and [18F] 6 hold promise for studying the μ-opioid receptor in humans by means of positron emission tomography.
- Henriksen, Gjermund,Platzer, Stefan,Marton, János,Hauser, Andrea,Berthele, Achim,Schwaiger, Markus,Marinelli, Luciana,Lavecchia, Antonio,Novellino, Ettore,Wester, Hans-Jürgen
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Read Online
- OPIOID HAPTENS, CONJUGATES, VACCINES, AND METHODS OF GENERATING ANTIBODIES
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The disclosure provides, inter alia, opioid haptens, opioid hapten conjugates, opioid vaccines, methods of treating or preventing opioid use disorder, methods of treating opioid overdose, and methods of generating and/or isolating antibodies selective for opioids.
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Paragraph 0259-0260
(2020/02/14)
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- Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors
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Aiming to develop novel Type-I1/2 inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC50 values of 0.06 and 0.23 μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALKWT (2.5 nM) and ALKL1196M (6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I1/2 inhibitor binding mode.
- Gong, Ping,Guo, Ming,Liu, Sicong,Miao, Xiuqi,Xing, Lingyun,Yin, Shiliang,Zhai, Xin,Zhang, Dajun,Zhang, Hong
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- 1,3,8-TRIAZASPIRO COMPOUNDS AND THEIR USE AS MEDICAMENTS FOR THE TREATMENT OF REPERFUSION INJURY
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The present invention relates to a 1,3,8-triazaspiro compound of Formula (I), wherein A is -CH2, -SO2 -, -NH-CO-, -NH-CS- or -CO-; the dashed line represents a single or double bond; R1 is a substituent selected from (C1-C3) alkyl, phenyl, thienyl and cyclohexyl, said substituent being optionally substituted by halogen or (C1 -C3) alkyl; and R2 is a substituent selected from H, (C1-C3) alkyl, (C1-C3) alkoxy, -CF3 and halogen; and wherein, when the dashed line is a double bond, A is -CH2 - and R1 is phenyl, or a pharmaceutically acceptable salt thereof for use in the treatment of reperfusion injury diseases. The 1,3,8-triazaspiro compound of the invention is a selective inhibitor of the C subunit of the F1/Fo-ATP synthase complex and a modulator of the mitochondrial permeability transition pore activity in mammalian cells and tissues, in the treatment of reperfusion injury diseases.
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Page/Page column 23-24
(2020/02/16)
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- Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F1/FO-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction
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Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.
- Morciano, Giampaolo,Preti, Delia,Pedriali, Gaia,Aquila, Giorgio,Missiroli, Sonia,Fantinati, Anna,Caroccia, Natascia,Pacifico, Salvatore,Bonora, Massimo,Talarico, Anna,Morganti, Claudia,Rizzo, Paola,Ferrari, Roberto,Wieckowski, Mariusz R.,Campo, Gianluca,Giorgi, Carlotta,Trapella, Claudio,Pinton, Paolo
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supporting information
p. 7131 - 7143
(2018/08/17)
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- Synthesis of Hindered α-Amino Carbonyls: Copper-Catalyzed Radical Addition with Nitroso Compounds
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The synthesis of sterically hindered anilines has been a significant challenge in organic chemistry. Here we report a Cu-catalyzed radical addition with in situ-generated nitroso compounds to prepare sterically hindered amines directly from readily available materials. The transformation is conducted at room temperature, uses abundant copper salts, and is tolerant of a range of functional groups.
- Fisher, David J.,Burnett, G. Leslie,Velasco, Rocío,Read De Alaniz, Javier
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supporting information
p. 11614 - 11617
(2015/09/28)
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- Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production of carfentanil, sufentanil, and remifentanil
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Two spirodiaza intermediates have been made and employed in the synthesis of 4-anilinopiperidine methyl esters. These intermediates can be utilized in the production of commercial synthetic analgesics carfentanil, sufentanil, and remifentanil.
- Walz, Andrew J.,Hsu, Fu-Lian
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supporting information
p. 501 - 502
(2014/01/06)
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- Synthesis of intermediate anilino methyl esters used in the production of synthetic opioid analgesics
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An improved process or method of synthesis of carfentanil and other potent opioid analgesics of the N-alkyl 4-substituted 4-piperidinylamide class which can be used as morphine substitutes.
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Page/Page column 3; 4
(2014/06/11)
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- SUBSTITUTED 4-AMINO-PIPERIDINES
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The present invention relates to new substituted 4-amino-piperidine opioid receptor modulators, pharmaceutical compositions thereof, and methods of use thereof
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Page/Page column 24
(2010/02/17)
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- A facile method for preparation of [2H3]-sufentanil and its metabolites
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An improved process for the synthesis of sufentanil with an overall yield of 26% is described. The reactive and high yielding N-debenzylation of the piperidine intermediate 7 using a mixture of Pd/C and Pd(OH)2 was applied to other drug intermediates affording free amines in short reaction times. The deuterium-labeled sufentanil and the metabolite desmethylsufentanil were synthesized applying the optimized process.
- Srimurugan, Sankareswaran,Murugan, Kaliyappan,Chen, Chinpiao
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experimental part
p. 1421 - 1424
(2010/06/14)
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- Piperidone derivatives and medical uses thereof
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The present invention relates to compositions comprising 4-Oxo-piperidine-carboxylates and derivatives thereof, for example derivatives substituted with phenyl, nitrophenyl or benzyl groups. It also teaches the medical use of these and related compounds for treatment of retroviral diseases, in particular, HIV and HTLV, proliferative diseases, in particular CML and Trypanosomiasis.
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Page/Page column 17; 24
(2009/04/23)
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- Aromatic amines as nucleophiles in the Bargellini reaction
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Aromatic amines can be employed in the Bargellini reaction to generate useful intermediates. Rapid, practical access to functionalised, privileged structures may have significant utility in the synthesis of drug-like molecules. An improved synthesis of carfentanil analogues illustrates this point.
- Butcher, Ken J.,Hurst, Jenny
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body text
p. 2497 - 2500
(2009/09/05)
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- IMPROVED METHOD OF MAKING SUFENTANIL
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The present invention relates to a process for the preparation of piperidine derivatives including sufentanil and its pharmaceutically acceptable salts, such as it citrate salt
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Page/Page column 2; 6
(2010/11/29)
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- In search of novel agents for therapy of tropical diseases and human immunodeficiency virus
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Malaria, sleeping sickness, Chagas' disease, Aleppo boil, and AIDS are among the tropical diseases causing millions of infections and cases of deaths per year because only inefficient chemotherapy is available. Since the targeting of the enzymes of the polyamine pathway may provide novel therapy options, we aimed to inhibit the deoxyhypusine hydroxylase, which is an important step in the biosynthesis of the eukaryotic initiation factor 5A. In order to identify new lead compounds, piperidines were produced and biologically evaluated. The 3,5-diethyl piperidone-3,5-dicarboxylates 11 and 13 substituted with 4-nitrophenyl rings in the 2 and 6 positions were found to be active against Trypanosoma brucei brucei and Plasmodium falciparum combined with low cytotoxicity against macrophages. The corresponding monocarboxylates are only highly active against the T. brucei brucei. The piperidine oximether 53 demonstrated the highest plasmodicidal activity. Moreover, compounds 11 and 53 were also able to inhibit replication of HIV-1.
- Goebel, Tim,Ulmer, Daniela,Projahn, Holger,Kloeckner, Jessica,Heller, Eberhard,Glaser, Melanie,Ponte-Sucre, Alicia,Specht, Sabine,Sarite, Salem Ramadan,Hoerauf, Achim,Kaiser, Annette,Hauber, Ilona,Hauber, Joachim,Holzgrabe, Ulrike
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p. 238 - 250
(2008/09/18)
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- MUSCARINIC MODULATORS
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The present invention relates to modulators of muscarinic receptors. The present invention also provides compositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.
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Page/Page column 56-57
(2010/11/24)
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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 33
(2010/02/13)
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- Synthesis and characterization of pseudopeptide bradykinin B2 receptor antagonists containing the 1,3,8-triazaspiro[4.5]decan-4-one ring system
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A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro2-Pro3-Gly4-Phe5 section of the peptide bradykinin B2 receptor antagonist [Pro3, Phe5]HOE 140 (D-Arg0-Arg1- Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7-Oic8-Arg9) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.
- Mavunkel, Babu J.,Lu, Zhijian,Goehring, R. Richard,Lu, Songfeng,Chakravarty, Sarvajit,Perumattam, John,Novotny, Elizabeth A.,Connolly, Maureen,Valentine, Heather,Kyle, Donald J.
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p. 3169 - 3173
(2007/10/03)
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- Synthesis and pharmacological evaluation of 4,4-disubstituted piperidines
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A new class of piperidine derivatives is added to the increasing family of compounds related to fentanyl and carfentanil. Herein, we describe the synthesis and pharmacology of a number of 1-(arylethyl)-4-(acylamino)-4-[(acyloxy)-methyl]piperidines such as 9, 15, and 23. As expected, many of these congeners of fentanyl are extremely potent narcotic agonists. The aim of the study was to identify short-acting analgesic agents (i.e. less than 6 min in the mouse hot-plate assay) for possible use in the surgical theater. Many of the drugs proved to be of intermediate and long duration (i.e. 6-15 min and > 15 min, respectively). In addition to analgesic activity, many of the compounds exhibited anesthetic properties as well. The structure-activity relationship for these entities is presented and discussed.
- Colapret,Diamantidis,Spencer,Spaulding,Rudo
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p. 968 - 974
(2007/10/02)
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