- Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
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Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
- Dol?ak, Ana,?ribar, Dora,Scheffler, Alexander,Grabowski, Maria,?vajger, Urban,Gobec, Stanislav,Holze, Janine,Weindl, Günther,Wolber, Gerhard,Sova, Matej
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- Synthesis and structure-activity relationship analysis of 5-HT7 receptor antagonists: Piperazin-1-yl substituted unfused heterobiaryls
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A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7 /5-HT2A R ligand, and 13 as a multi-receptor (5-HT7 , 5-HT2A , 5-HT6 and D2 ) agent.
- Strekowski, Lucjan,Saczewski, Jaros?aw,Raux, Elizabeth A.,Fernando, Nilmi T.,Klenc, Jeff,Paranjpe, Shirish,Raszkiewicz, Aldona,Blake, Ava L.,Ehalt, Adam J.,Barnes, Samuel,Baranowski, Timothy C.,Sullivan, Shannon M.,Sata?a, Grzegorz,Bojarski, Andrzej J.
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- Palladium-catalyzed cross-couplings of lithium arylzincates with aromatic halides: Synthesis of analogues of isomeridianin G and evaluation as GSK-3β inhibitors
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Several analogues of isomeridianin G have been synthesized using palladium-catalyzed cross-coupling reactions of lithium triorganozincates as a key step. The latter have been prepared by deprotonative lithiation followed by transmetalation using ZnCl
- Seggio, Anne,Priem, Ghislaine,Chevallier, Floris,Mongin, Florence
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experimental part
p. 3617 - 3632
(2010/03/05)
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- SUBSTITUTED PYRIMIDINE COMPOUNDS AND THEIR USE AS IFNAR MEDIATORS
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The present application relates to substituted pyrimidine compounds of Formula I and their use as ligands for IFNAR. The application further relates to methods of treating or preventing diseases or disorders that benefit from the modulation of IFNAR by ad
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Page/Page column 18-19
(2009/10/22)
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- Synthesis of unsymmetrical heterobiaryls using palladium-catalyzed cross-coupling reactions of lithium organozincates
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Several unsymmetrical heterobiaryls have been synthesized through palladium-catalyzed cross-coupling reactions of lithium triorganozincates. The latter have been prepared by deprotonative lithiation followed by transmetalation using non-hygroscopic ZnCl2-TMEDA (0.33 equiv). Georg Thieme Verlag Stuttgart.
- Seggio, Anne,Jutand, Anny,Priem, Ghislaine,Mongin, Florence
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experimental part
p. 2955 - 2960
(2009/06/27)
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- Inhibitors of Hepatitis C Virus
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Macrocyclic peptides are disclosed having the general formula: wherein R3, R3′, R4, R6, R′, X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 66
(2008/12/04)
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- De novo design of nonpeptidic compounds targeting the interactions between interferon-α and its cognate cell surface receptor
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Type 1 interferons (IFN) bind specifically to the corresponding receptor, IFNAR. Agonists and antagonists for IFNAR have potential therapeutic value in the treatment of viral infections and systemic lupus erythematosus, respectively. Specific sequences on
- Bello, Angelica M.,Bende, Tanushree,Wei, Lianhu,Wang, Xiaoyang,Majchrzak-Kita, Beata,Fish, Eleanor N.,Kotra, Lakshmi P.
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p. 2734 - 2743
(2008/12/22)
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- Hepatitis C virus inhibitors
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Macrocyclic peptides are disclosed having the general formula: wherein R′, R3, R3′, R4, R6, X, Q, and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 66-67
(2010/11/26)
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- Hepatitis C virus inhibitors
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which inhibit the function of the NS3 protease (also referred to herein as “serine protease”) encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS3 protease.
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Page/Page column 77
(2008/06/13)
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- PYRIMIDIN-2-ONE COMPOUNDS AND THEIR USE AS DOPAMINE D3 RECEPTOR LIGANDS
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The invention relates to pyrimidin-2-one compounds of general formula (I), in addition to the derivatives and tautomers of (I) and the physiologically acceptable salts of said compounds. In said formula: A represents linear or branched C3-C6 alkene, which can have a double bond or triple bond and/or a group Z, which is not adjacent to the nitrogen atom of the pyrimidinone ring and is selected from O, S, C(O), NR3, C(O)NR3, NR3C(O), OC(O) and C(O)O; B represents a group of formula (II), in which X stands for CH2 or N and Y stands for CH2 or CH2CH2, or X-Y can also jointly represent C=CH, C=CH-CH2 or CH-CH=CH; R1 and R 2 are defined as cited in the description and the claims; and Ar represents an optionally substituted aromatic group. The invention also relates to a pharmaceutical agent, containing at least one compound (I) and the tautomers, derivatives and/or acid addition salts of said compound, optionally together with physiologically acceptable carriers and/or auxiliary agents. The invention also relates to the use of compounds of formula (I), and their tautomers, derivatives and pharmacologically acceptable acid addition salts for producing a pharmaceutical agent for treating diseases, which respond to the influence of dopamine D3 receptor ligands.
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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Page 447-448
(2008/06/13)
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- Synthesis of 2-Chloro-4,6-di(heteroaryl)pyrimidines
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A practical method for the preparation of 2-chloro-4,6-di(heteroaryl)pyrimidines and their 5-methyl homologues from readily available 2-chloropyrimidine and 2-chloro-5-methylpyrimidine, respectively, is described.The method is based on the addition reactions of heteroaryllithium reagents with chloropyrimidines followed by dehydrogenation of the resultant substituted dihydropyrimidines.The use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the dehydrogenation agent gives the best results.Side reactions in the addition step are discussed.
- Strekowski, Lucjan,Harden, Donald B.,Grubb, William B.,Patterson, Steven E.,Czarny, Agnieszka,et al.
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p. 1393 - 1400
(2007/10/02)
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