- Rational design of selective inhibitors of PARP4
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PARPs (PARP1-16 in humans) are a large family of ADP-ribosyltransferases (ARTs) that have diverse roles in cellular physiology and pathophysiology. Most PARP family members mediate mono-ADP-ribosylation (MARylation) of targets. The function of PARP-mediated MARylation in cells is poorly characterized, due in large part to the paucity of selective small molecule inhibitors of the catalytic activity of individual PARP enzymes. Herein we describe the rational design of selective small molecule inhibitors of PARP4 (also known as vPARP). These inhibitors are based on a quinazolin-4(3H)-one scaffold, and contain substituents at the C-8 position designed to exploit a unique threonine (Thr484, human PARP4 numbering) in the PARP4 nicotinamide sub-pocket. Our most potent analog, AEP07, which contains an iodine at the C-8 position, is at least 12-fold selective over other PARP family members. AEP07 will serve as a useful lead compound for the further development of PARP4 inhibitors that can be used to probe the cellular functions of PARP4 catalytic activity. This journal is
- Cohen, Michael,Kirby, Ilsa T.,Person, Ashley
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p. 1950 - 1957
(2021/12/24)
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- Tunable Electrosynthesis of Anthranilic Acid Derivatives via a C-C Bond Cleavage of Isatins
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A facile and direct electrocatalytic C-C bond cleavage/functionalization reaction of isatins was developed. With isatins as the amino-attached C1 sources, a variety of aminobenzoates, and aminobenzamides were synthesized in moderate to good yields under mild conditions.
- Qian, Peng,Liu, Jiaojiao,Zhang, Yan,Wang, Zhiyong
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p. 16008 - 16015
(2021/07/31)
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- PARP INHIBITORS FOR TREATING CANCER AND ASTHMA
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Provided are substituted 8-methylquinazolin-4(3H)-one compounds useful as PARP inhibitors for the treatment of cancer and asthma, as well as pharmaceutical compositions comprising them and methods for their synthesis.
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Page/Page column 21; 23; 24
(2020/03/23)
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- Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators
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Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.
- Pinkerton, Anthony B.,Peddibhotla, Satyamaheshwar,Yamamoto, Fusayo,Slosky, Lauren M.,Bai, Yushi,Maloney, Patrick,Hershberger, Paul,Hedrick, Michael P.,Falter, Bekhi,Ardecky, Robert J.,Smith, Layton H.,Chung, Thomas D. Y.,Jackson, Michael R.,Caron, Marc G.,Barak, Lawrence S.
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supporting information
p. 8357 - 8363
(2019/09/10)
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- Four new amide derivatives of pyridinecarboxylic acids. Synthesis, structure and spectroscopic characterization
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This study treats about four new pyridine amide derivatives obtained by a simple and inexpensive method of synthesis which consisted in amide coupling of pyridine-2-carboxylic acid and pyridine-4-carboxylic acid chlorides and aromatic amines: methyl 2-amino-3-methylbenzoate (Ea), methyl 3-amino-2-methylbenzoate (Eb), methyl 3-amino-4-methylbenzoate (Ec). All products of synthesis: L1, L2, L3, L4 were analyzed in detail by FT-IR, 1H, 13C, COSY 2D, HSQC, HMBC NMR spectroscopy, elemental, TGA and X-ray analysis. The excitation and emission spectra for obtained amides were also registered. An exact examination of results confirmed receiving four amide compounds with higher potential ability to metal ion coordination than the substrates alone.
- Kwiatek, Dorota,Kubicki, Maciej,Barczyński, Piotr,Lis, Stefan,Hnatejko, Zbigniew
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- Asymmetric Synthesis of Fused Polycyclic Indazoles through Aminocatalyzed Aza-Michael Addition/Intramolecular Cyclization
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The first example of an asymmetric aminocatalyzed aza-Michael addition of 1H-indazole derivatives to α,β-unsaturated aldehydes is described. The iminium/enamine cascade process lies at the heart of our strategy, leading to enantioenriched fused polycyclic indazole architectures. Variations on both the α,β-unsaturated aldehydes and the indazole-7-carbaldehyde heterocycles were studied in order to broaden the scope of the transformation in synthetically interesting directions. The fused polycyclic indazoles exhibit fluorescence properties and can undergo synthetic transformations.
- Giardinetti, Maxime,Marrot, Jér?me,Moreau, Xavier,Coeffard, Vincent,Greck, Christine
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p. 6855 - 6861
(2016/08/16)
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- QUINOLINYL MODULATORS OF RORyt
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The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.
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Paragraph 0685; 0686
(2015/04/28)
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- Tandem C-O and C-N Bonds Formation Through O-Arylation and [3,3]-Rearrangement by Diaryliodonium Salts: Synthesis of N-Aryl Benzo[1,2,3]triazin-4(1H)-one Derivatives
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Metal-free O-arylation and [3, 3]-rearrangement have been shown as an efficient strategy to construct new C-O and C-N bonds in one-pot reactions. The method was used to prepare N-aryl benzo[1,2,3]triazin-4(1H)-one derivatives in good yields from N-hydroxy benzo[1,2,3]triazin-4(3H)-one and diaryliodonium salts. The reaction was tolerated a variety of sensitive functional groups such as iodine, nitro, ester, and aldehyde groups. A rational mechanism was proposed based on the experimental results, and the reaction was easily up to gram scale.
- Shi, Wei-Min,Ma, Xiao-Pan,Pan, Cheng-Xue,Su, Gui-Fa,Mo, Dong-Liang
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p. 11175 - 11183
(2015/11/18)
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- Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
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N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
- Hansen, Martin,Jacobsen, Stine Engesgaard,Plunkett, Shane,Liebscher, Gudrun Eckhard,McCorvy, John D.,Br?uner-Osborne, Hans,Kristensen, Jesper Langgaard
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supporting information
p. 3933 - 3937
(2015/01/30)
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- One-pot synthesis of novel 3,5-disubstituted-1,2,4-oxadiazoles from indazole carboxylic acid esters and amidoximes
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An efficient and high-yielding one-pot synthesis of 3,5-disubstituted-1,2, 4-oxadiazoles from indazole carboxylic acid methyl esters and amidoximes is described. In this study a series of novel 3,5-disubstituted-1,2,4-oxadiazoles (3a-d), (4a-d), (5a-d), (6a-d), (7a-d) were synthesized using amidoximes 2a-d and indazole carboxylic acid esters (3-6).
- Swamy, Udutha Kumara,Mohan, H. Rama,Prasad, U. Viplava,Suresh,Kumar, T. Laxmi
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p. 1921 - 1930
(2014/06/09)
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- Chemoselective reduction and self-immolation based FRET probes for detecting hydrogen sulfide in solution and in cells
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Hydrogen sulfide (H2S) has been regarded as the third gaseous transmitter. Based on the mechanism of chemoselective azido reduction and self-immolation, five fluorescence resonance energy transfer (FRET) probes for the detection of H2S were designed and synthesized. The effect of functional substitution of the self-immolative moiety on azido reduction and quinone-methide rearrangement were investigated. Their fluorescence responses and chemoselectivity for H2S detection were evaluated in solutions and in cells. This strategy may provide a general route for designing H 2S probes with many commercially available FRET pairs. the Partner Organisations 2014.
- Chen, Bifeng,Wang, Peng,Jin, Qingqing,Tang, Xinjing
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supporting information
p. 5629 - 5633
(2014/07/22)
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- A significant improvement in enantioselectivity, yield, and reactivity for the copper-bi-o-tolyl bisoxazoline-catalyzed asymmetric allylic oxidation of cyclic olefins using recoverable SBA-15 mesoporous silica material
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A series of chiral bi-o-tolyl bisoxazoline ligands 1 and 2 were conveniently synthesized on a gram scale from inexpensive and commercially available 3-methyl benzoic acid in eight steps. The catalytic and induced asymmetric effects of the chiral copper (I) complexes of these ligands on the asymmetric allylic oxidation of cycloolefins were investigated in the presence of various nano-sized additives. When SBA-15 mesoporous silica was used in conjunction with these ligands very highly enantioselectivities (up to 97% ee) and excellent yields (up to 99%) of the corresponding chiral allylic esters were obtained in a reasonably short period of time.
- Samadi, Saadi,Nazari, Saber,Arvinnezhad, Hamid,Jadidi, Khosrow,Notash, Behrouz
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p. 6679 - 6686
(2013/07/26)
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- Broensted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans
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Broensted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans has been developed. This method operates via the in situ formation of aminobenzylfuran, followed by its recyclization into the indole core. The method proved to be efficient for substrates possessing different functional groups, including -OMe, -CO2Cy, and -Br. The resulting indoles can easily be transformed into diverse scaffolds, including 2,3- and 1,2-fused indoles, and indoles possessing an α,β-unsaturated ketone moiety at the C-2 position.
- Kuznetsov, Alexey,Makarov, Anton,Rubtsov, Aleksandr E.,Butin, Alexander V.,Gevorgyan, Vladimir
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p. 12144 - 12153
(2014/01/06)
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- Design, synthesis and identification of novel colchicine-derived immunosuppressant
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Synthesis and biological evaluation of various colchicine analogues through the mixed-lymphocyte reaction (MLR), lymphoproliferation, and inhibitory effects on the inflammatory genes are described. In addition, a new series of immunosuppressive agents developed on the structural basis of colchicine, as well as their structure-activity relationships is reported. The most potent analogue 20a exhibited an excellent immunosuppressive activity on in vivo skin-allograft model, which is comparable to that of cyclosporin A.
- Chang, Dong-Jo,Yoon, Eun-Young,Lee, Geon-Bong,Kim, Soon-Ok,Kim, Wan-Joo,Kim, Young-Myeong,Jung, Jong-Wha,An, Hongchan,Suh, Young-Ger
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scheme or table
p. 4416 - 4420
(2010/04/05)
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- Parallel synthesis and spectroscopic analysis of a collection of heterocycles based on the diazabenz[e]aceanthrylene core structure
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A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.
- Jones, Alan M.,Lebl, Tomas,Patterson, Stephen,van Mourik, Tanja,Früchtl, Herbert A.,Philp, Douglas,Slawin, Alexandra M.Z.,Westwood, Nicholas J.
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supporting information; experimental part
p. 563 - 578
(2009/04/06)
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- SPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS
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The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating mammals suffering from the condition of being overweight.
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Page/Page column 27-28
(2008/12/06)
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- UREA DERIVATIVE
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The present invention relates to a urea derivative or a pharmacologically acceptable salt thereof having an excellent DGAT inhibitory effect. A urea derivative having the formula: [wherein R 1 is a C 6 -C 10 aryl group which may be independently mono- to pentasubstituted by a group selected from Substituent Group a or others; R 2 is a C 6 -C 10 aryl group which may be independently mono- to pentasubstituted by a group selected from Substituent Group a or others; E is a group having the formula (II) or the formula (III) (wherein R 3 is a hydrogen atom or others; R 4 and R 5 , which are the same or different, are a hydrogen atom or others; X and U, which are the same or different, are a group represented by the formula CH or others; m and n, which are the same or different, are 1 or another number) or others; and A is a group represented by the formula -NH-C(=O)- or others], or a pharmacologically acceptable salt thereof.
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Page/Page column 142
(2010/11/26)
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- INDOLE AMIDE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
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The invention is directed to indole amide derivatives as EP4 receptor antagonists useful for the treatment of EP4 mediated diseases or conditions, such as acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer. Pharmaceutical compositions and methods of use are also included.
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Page/Page column 29
(2008/06/13)
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- METHOD FOR PREPARING N-PHENYLPYRAZOLE-1-CARBOXAMIDES
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A method is disclosed for preparing compounds of Formula (I) by combining compounds of Formulae (II and III) and a sulfonyl chloride. Also disclosed are compounds of Formula (III), which are useful as starting materials for this method.
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Page/Page column 23
(2008/06/13)
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- SUBSTITUTED ISOQUINOLINONES
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Isoquinolinone compounds are provided that are useful for the inhibition of ADP-platelet aggregation, particularly in the treatment of thrombosis and thrombosis related conditions or disorders.
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Page/Page column 81
(2010/02/11)
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- INDAZOLES, BENZOTHIAZOLES, BENZOISOTHIAZOLES, BENZISOXAZOLES, AND PREPARATION AND USES THEREOF
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 77-79
(2010/02/14)
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- Phenylpyrroles, a new chemolibrary virtual screening class of 5-HT 7 receptor ligands
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Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.
- Paillet-Loilier, Magalie,Fabis, Frederic,Lepailleur, Alban,Bureau, Ronan,Butt-Gueulle, Sabrina,Dauphin, Francois,Delarue, Catherine,Vaudry, Hubert,Rault, Sylvain
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p. 3753 - 3757
(2007/10/03)
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- INDAZOLES, BENZOTHIAZOLES, AND BENZOISOTHIAZOLES, AND PREPARATION AND USES THEREOF
-
The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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- Fungicidal cyclic amides
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Cyclic amides, including triazole containing cyclic amides, their N-oxides, agriculturally-suitable salts and compositions, and their methods of use as fungicides.
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- 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically Active Anticonvulsants Acting by Antagonism at the Glycine Site of the N-Methyl-D-Aspartate Receptor Complex
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Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier.By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one.In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 for displacement of -L-689,560 binding of 0.17 μM and Kb against NMDA in the cortical slice of 1.39 μM.Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip.A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the ?-system of the 3-substituent.
- Rowley, Michael,Leeson, Paul D.,Stevenson, Graeme I.,Moseley, Angela M.,Stansfield, Ian,et al.
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p. 3386 - 3396
(2007/10/02)
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- Herbicidal N-haloacetyl-2-methyl-6-substituted methoxymethylanilines
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Compounds of the formula STR1 wherein R1 is alkyl or alkoxy; R2 is alkenyl having 2 to 10 carbon atoms, substituted alkyl of 1 to 10 carbon atoms or substituted alkenyl of 1 to 10 carbon atoms substituted with 1 or 2 hydroxy groups or 1 or 2 alkoxy groups of 1 to 4 carbon atoms or 1 or 2 alkenyloxy groups of 2 to 4 carbon atoms; acyl, and ketal group of the formula STR2 wherein n=2, 3 or 4, R4 is alkyl and R5 is hydrogen or alkyl, an oxime of the formula STR3 wherein R6 is hydrogen or alkyl; R3 is hydrogen or alkyl; X is halo have herbicidal activity.
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