26830-94-4Relevant academic research and scientific papers
Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
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
, p. 481 - 515 (2021/02/05)
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.
Boron Containing PDE4 Inhibitors
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Paragraph 0767-0768, (2020/04/29)
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.
INHIBITORS OF N-ACYLPHOSPHATIDYLETHANOLAMINE PHOSPHOLIPASE D (NAPE-PLD)
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, (2019/12/15)
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.
Design, synthesis and evaluation of novel derivatives of orotic acid amide as potent glucokinase activators
Zhang, Leilei,Hu, Shengquan,Lei, Lei,Zhang, Yuliang,Zhang, Lijing,Song, Hongrui,Shen, Zhufang,Feng, Zhiqiang
, p. 252 - 261 (2017/02/15)
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.
PYRIDINES AND PYRIMIDINES AND USE THEREOF
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Paragraph 0260; 0261, (2017/01/31)
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.
Carboxamide Derivatives and Use Thereof
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Paragraph 1126; 1127, (2016/02/21)
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
PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
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Page/Page column 111, (2016/07/05)
Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
AZASPIRO[4.5] DECANE DERIVATIVES AND USE THEREOF
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Page/Page column 72; 73, (2015/03/16)
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
DIBENZAZEPINE DERIVATIVES AND USE THEREOF
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Paragraph 0321, (2015/07/02)
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
INDAZOLES AND USE THEREOF
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Page/Page column 62, (2015/07/15)
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
