- Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
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N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [ Mock et al. Nat Chem. Biol., 2020, 16, 667-675 ]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo.
- Mock, Elliot D.,Kotsogianni, Ioli,Driever, Wouter P. F.,Fonseca, Carmen S.,Vooijs, Jelle M.,Den Dulk, Hans,Van Boeckel, Constant A. A.,Van Der Stelt, Mario
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p. 481 - 515
(2021/02/05)
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- Boron Containing PDE4 Inhibitors
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The present invention relates to boron containing compounds of Formula (I) [in-line-formulae]X—Y—Z?? Formula (I)[/in-line-formulae] that inhibit phosphodiesterase 4 (PDE4). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating diseases, conditions, or disorders ameliorated by inhibition of PDE4.
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Paragraph 0767-0768
(2020/04/29)
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- INHIBITORS OF N-ACYLPHOSPHATIDYLETHANOLAMINE PHOSPHOLIPASE D (NAPE-PLD)
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The invention relates to a compound of the formula (I) as novel inhibitor of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), and to use thereof for the prophylaxis or treatment of diseases associated with NAPE-PLD. wherein in a ring A, X1 is N, or CR4; X2 is N or CR5; X3 is N or CH; with the proviso that at least one of X1 and X3 is N.
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- Design, synthesis and evaluation of novel derivatives of orotic acid amide as potent glucokinase activators
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Background: Glucokinase activators (GKAs) represent a promising opportunity for the treatment of type 2 diabetes due to the fact that glucokinase (GK) is a key regulator of glucose homeostasis. Method: Based on structure-based design strategies, a series of novel orotic acid amide derivatives have been synthesized. Lead optimization led to the discovery of several active compounds via in vitro enzyme assays. Compared to the positive control compound GKA22, compounds 10j, 11h and 11i exhibited identical or even higher activity. Furthermore, docking simulation of compound 11i further demonstrated that the hydrogen atom of amide and the nitrogen atom of pyrimidine both bound to Arg63 via hydrogen bonds. Results: Hydrogen bond interactions were also observed between the two oxygen atoms of 2-methoxy-1-methyl-ethoxy moiety and Thr65. Both ends of the molecule were fixed in allosteric pocket of glucokinase, which was in favour of keeping active conformation.
- Zhang, Leilei,Hu, Shengquan,Lei, Lei,Zhang, Yuliang,Zhang, Lijing,Song, Hongrui,Shen, Zhufang,Feng, Zhiqiang
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p. 252 - 261
(2017/02/15)
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- PYRIDINES AND PYRIMIDINES AND USE THEREOF
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The present disclosure provides pyridines and pyrimidines of Formula I and pharmaceutically acceptable salts and solvates thereof: wherein A, G, W1, W2, W3, and R5 are defined as set forth in the specification. The present disclosure also provides uses of the compounds of Formula I and pharmaceutically acceptable salts and solvates thereof. In certain embodiments, Compounds of the present disclosure are useful for treating pain. In another embodiment, Compounds of the present disclosure are useful for treating a disorder responsive to blockade of sodium channels, or alleviating symptoms of the disorder.
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Paragraph 0260; 0261
(2017/01/31)
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- Carboxamide Derivatives and Use Thereof
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The present disclosure provides substituted pyridyl-, pyrimidinyl-, pyrazinyl-, pyridazinyl-, and triazinyl-based carboxamides of Formula I-A: R10 Z-HET-E I-A and the pharmaceutically acceptable salts and solvates thereof, wherein Z, HET, Rsup
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Paragraph 1126; 1127
(2016/02/21)
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- PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
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Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Page/Page column 111
(2016/07/05)
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- Effect of water solvation on the lipophilicity of isomeric pyrimidine-carboxamides
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Abstract Incorporation of nitrogen is a common medicinal chemistry tactic to reduce log D values. Neighboring group participation influences log D, so the results are isomer dependent. The log D and log P differences observed between isomeric pyrimidines 1, 2 and 3 presumably result when the carbonyl or ether lone pairs are in close proximity to a heterocyclic nitrogen lone pair, recruiting water to bridge between the electron rich atoms. Various lipophilicity calculators did not discriminate between 1 (log D = 2.6) and 3 (log D = 1.0), but solvation energies using Poisson-Boltzmann and 3D-RISM methods rationalize the observed differences in lipophilicity among pyrimidine carboxamide isomers.
- Linton, Maria Angelica,Burke, Benjamin J.,Johnson, Ted W.,Ninkovic, Sacha,Gajiwala, Ketan S.,Richardson, Paul,Le, Phuong T.
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p. 3408 - 3413
(2015/08/03)
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- AZASPIRO[4.5] DECANE DERIVATIVES AND USE THEREOF
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The invention provides azaspiro[4.5]decane derivatives of Formula (A): and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, wherein A1, X, A2, Rr, R2', W1, W2/sup
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Page/Page column 72; 73
(2015/03/16)
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- DIBENZAZEPINE DERIVATIVES AND USE THEREOF
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The present disclosure provides dibenzazepine derivatives having Formula I or I(A): and the pharmaceutically acceptable salts and solvates thereof, wherein R3a, R3b, R6, V1, V2, Z1, Z2
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Paragraph 0321
(2015/07/02)
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- INDAZOLES AND USE THEREOF
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In one aspect, the present disclosure provides indazoles of Formula I: (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R3, R4, R5, R6, Z1, Z2, Z3, and
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Page/Page column 62
(2015/07/15)
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- PYRIDINES AND PYRIMIDINES AND USE THEREOF
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The present disclosure provides pyridines and pyrimidines of Formula I and pharmaceutically acceptable salts and solvates thereof: wherein A, G, W1, W2, W3, and R5 are defined as set forth in the specification. The present disclosure also provides uses of the compounds of Formula I and pharmaceutically acceptable salts and solvates thereof. In certain embodiments, Compounds of the present disclosure are useful for treating pain. In another embodiment, Compounds of the present disclosure are useful for treating a disorder responsive to blockade of sodium channels, or alleviating symptoms of the disorder.
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Page/Page column 66-67
(2015/08/06)
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- ISOQUINOLINE DERIVATIVES AND USE THEREOF
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The Invention provides compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof: wherein W1, W2, W3, J1, J2, A, R1, R2/su
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Page/Page column 63
(2015/09/22)
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- INDOLE DERIVATIVES AND USE THEREOF
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The Invention provides indole derivatives of Formula I: and pharmaceutically acceptable salts and solvates thereof, wherein R1e, R1f, A, X, Y, Z, and W4 are defined as set forth in the specification. The Invention also pro
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Paragraph 0302; 0303
(2015/10/28)
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- PYRIMIDINE CARBOXAMIDES AS SODIUM CHANNEL BLOCKERS
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The present disclosure provides substituted pyrimidine carboxamides of Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein A1, X, A2, W1, W2, W3, E, Z, and R4 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.
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Paragraph 0311
(2014/09/29)
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- PYRIMIDINES AS SODIUM CHANNEL BLOCKERS
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The present disclosure provides substituted pyrimidine compounds of Formula (I), and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein A1, X, A2, W1, W2, W3, E, Z, and R4 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.
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Page/Page column 104; 105
(2013/03/28)
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- PYRIMIDINE DIOL AMIDES AS SODIUM CHANNEL BLOCKERS
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The present disclosure provides pyrimidine diol amides of Formula (I), and the pharmaceutically acceptable solvates and prodrugs thereof, wherein A1, X, A2, W1, W2, W3, R1, R2, and R4 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.
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Page/Page column 93
(2013/06/05)
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- CGRP ANTAGONISTS
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The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R1, R2 and R3 are defined as stated hereinafter, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
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Page/Page column 96
(2011/04/18)
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- Total synthesis of (±)-cylindrospermopsin
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The first total synthesis of the novel hepatotoxin (±)- cylindrospermopson (1) has been accomplished in 20 steps from 4-methoxy-3- methylpyridine (12) in 3.5% overall yield. The substituted piperidine A ring 19 was generated stereospecifically by a four-step sequence using the addition of trimethylsilylethynylmagnesium bromide to 12 to give 16 and stereospecific addition of vinylcuprate to 16 to form 17. The reaction of diamine 26 with cyanogen bromide produced the cyclic guanidine C ring of 27. The key step in the synthesis was bromination of ketone 31, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular S(N)2 reaction to form the tetrahydropyrimidine ring B of 32. Further hydrogenation reduced the ketone to yield 42% of 32 containing the fully functionalized tricyclic system and protected hydroxymethyluracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine in concentrated hydrochloric acid and selective monosulfation completed the synthesis of cylindrospermopsin.
- Xie, Chaoyu,Runnegar, Maria T. C.,Snider, Barry B.
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p. 5017 - 5024
(2007/10/03)
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- DIAZOCARBONYL DERIVATIVES OF HETEROCYCLES. 7. SYNTHESIS, PROPERTIES, AND STRUCTURE OF 2,4-DIAZIDO-6-DIAZOACETYLPYRIMIDINE
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The reaction of 2,4-dichloro-6-diazoacetylpyrimidine with sodium azide to give 2,4-diazido-6-diazoacetylpyrimidine has been examined, and the crystal structure of the latter, and its 1,3-dipolar cycloadditions at the carbonyl group, studied.
- Kartsev, V. G.,Aliev, Z. G.,Voronina, G. N.,Atovmyan, L. O.
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p. 441 - 445
(2007/10/02)
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