- 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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- 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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- ANTI-BACTERIAL COMPOSITIONS AND METHODS INCLUDING TARGETING VIRULENCE FACTORS OF STAPHYLOCOCCUS AUREUS
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This disclosure relates to compositions and methods including for the inhibition, prevention, and/or treatment of microbial infections, including infections from such pathogens as Staphylococcus aureus.
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Page/Page column 25
(2012/02/03)
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- Design and synthesis of inhibitors of noroviruses by scaffold hopping
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A scaffold hopping strategy was employed to identify new chemotypes that inhibit noroviruses. The replacement of the cyclosulfamide scaffold by an array of heterocyclic scaffolds lead to the identification of additional series of compounds that possessed anti-norovirus activity in a cell-based replicon system.
- Dou, Dengfeng,Mandadapu, Sivakoteswara Rao,Alliston, Kevin R.,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
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experimental part
p. 5749 - 5755
(2011/10/31)
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- Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: In vitro, in vivo, and crystallographic results
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The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first co
- Song, Yongcheng,Liu, Chia-I.,Lin, Fu-Yang,Joo, Hwan No,Hensler, Mary,Liu, Yi-Liang,Jeng, Wen-Yih,Low, Jennifer,Liu, George Y.,Nizet, Victor,Wang, Andrew H.-J.,Oldfield, Eric
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experimental part
p. 3869 - 3880
(2009/12/28)
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- Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives
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A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKAy mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-γ. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4- phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p0.01) and plasma triglycelide levels (43%, p0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.
- Imoto, Hiroshi,Imamiya, Eikoh,Momose, Yu,Sugiyama, Yasuo,Kimura, Hiroyuki,Sohda, Takashi
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p. 1349 - 1357
(2007/10/03)
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- Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity
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This invention provides a novel oxyiminoalkanoic acid derivative which has excellent hypoglycemic and hypolipidemic actions and which is used for the treatment of diabetes mellitus, hyperlipemia, insulin insensitivity, insulin resistance and impaired glucose tolerance.
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- Physicochemical factors affecting the uptake by roots and translocation to shoots of amine bases in Barley
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The uptake by barley roots from nutrient solution and subsequent transport to shoots of two series of amine bases were measured over 6 to 72 h. The compounds were chosen to span systematically ranges of lipophilicity (assessed using 1-octanol/water partition coefficients, K(ow)) and pKa that would include commercial pesticide amines. In a series of six substituted phenethylamines, strong bases with pKa ~ 9.5, all the compounds were strongly taken up by roots from solutions of pH 8.0; uptake declined substantially as the pH was lowered to 5.0, especially for the compounds of intermediate lipophilicity (log K(ow)8 2 to 3). This uptake could be ascribed to three processes: (i) accumulation of the cation inside the root cells due to the negative charge on the plasmalemma, as given by the Nernst equation and important only for the polar compounds which have low permeation rates through membranes; (ii) accumulation into the vacuole by ion-trapping, which was the dominant process at high pH for all compounds and at all pH values for the compounds of intermediate lipophilicity; (iii) partitioning on to the root solids, substantial only for the most lipophilic compounds. Translocation to shoots was proportional to uptake by roots, this ratio being independent of external pH for each compound and being optimal for the compounds of intermediate lipophilicity. Such proportionality was also observed in a series of three weaker bases of intermediate lipophilicity, in which compounds of pKa 7.4 to 8.0 were also well taken up and translocated whereas the very weak base 4-ethylaniline (pKa 5-03) was much less so. Tests with quaternised pyridines confirmed that organic cations move only slowly through membranes. The observed behaviour of the amines could be modelled reasonably well assuming that transport within the plant was dominated by movement across membranes of the non-ionised species, and this appeared to be true even for the most lipophilic phenethylamine (log K(ow) 4.67) studied, though its long-distance movement would be as the protonated species.
- Inoue,Chamberlain,Bromilow
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- SYNTHESIS OF BENZYL ESTERS OF 2,2-DIMETHYL-3-(4-DIFLUOROMETHOXYPHENYL)CYCLOPROPANE CARBOXYLIC ACID - CYCLIC ANALOGS OF PYRETHROID FLUOROCITRINATE
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3-Phenoxybenzyl and α-cyano-3-phenoxybenzyl esters of 2,2-dimethyl-3-(4-difluoromethoxyphenyl)cyclopropane carboxylic acid have been synthesized.The latter compound, which is the cyclopropane analog of pyrethroid fluorocitrinate, has moderate insecticide activity toward the housefly.
- Shapiro, E. A.,Eismont, M. Yu.,Pereverzeva, Yu. O.,Nefedov, A. O.,Srashnenko, A. V.,et al.
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p. 573 - 577
(2007/10/02)
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- CYANATION OF HALO DERIVATIVES BY ACETONE CYANOHYDRIN
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A preparative method is proposed for the synthesis of substituted acetonitriles by the cyanation of halo derivatives by acetone cyanohydrin in the presence of base and phase transfer catalysts.
- Shapiro, E. A.,Pereverzeva, Yu. O.,Nefedov, A. O.,Eismont, M. Yu.
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p. 2432 - 2433
(2007/10/02)
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- HIGHLY REGIOSELECTIVE AROMATIC SUBSTITUTION ON A DIARYLOXIDETRICARBONYLCHROMIUM COMPLEX
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Ortho-substituted diaryloxide tricarbonylchromium (0) complexes PhOAr-Cr(CO)3, treated with carbanions Nu(-), give, after acid quenching, paradisubstituted complexes NuAr-Cr(CO)3 via a 1,3-hydride migration followed by elimination of phenol: the overall sequence of the reaction consists in a regioselective meta substitution of the phenoxy group by the nucleophile.
- Boutonnet, Jean-Charles,Rose-Munch, Francoise,Rose, Eric
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p. 3989 - 3992
(2007/10/02)
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