Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase

Ye, Bin; Bauman, John G.; Chen, Ming; Davey, David D.; Khim, Seock-Kyu; King, Beverly; Kirkland, Thomas A.; Kochanny, Monica J.; Liang, Amy; Lentz, Dao; May, Karen; Mendoza, Lisa M.; Phillips, Gary B.; Selchau, Victor; Schlyer, Sabine; Tseng, Jih-Lie; Wei, Robert G.; Ye, Hong; Parkinson, John F.; Guilford, William H.

doi:10.1016/j.bmcl.2008.06.046

Cited by 14 publications

(6 citation statements)

References 16 publications

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“…For example, NO 2 of 5a forms a hydrogen bond to Arg563. This binding mode corresponded with other peoples' docking results 31 and can be seen in crystal structures (PDB code 2R59 and 3B7R). 17 (3) Compounds possessing both o-and m-substituted groups on the terminal aryl ring (5d, 5j) cannot enter the long and narrow substrate channel of LTA 4 H, so they did not show inhibition activities to LTA 4 H. (4) When the compounds have large substituted group such as methylsulfonyl or aminomethanesulfonyl (5g, 5h, 5i, 7a, 7b, 8c, 13a), inhibition activities to LTA 4 H of the compounds were lower except 8c gave an IC 50 value 3.4 μM.…”

Section: ' Discussionsupporting

confidence: 84%

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase

Chen

Liu

et al. 2011

J. Med. Chem.

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Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.

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Section: ' Discussionsupporting

confidence: 84%

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase

Chen

Liu

et al. 2011

J. Med. Chem.

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“…Single nucleotide polymorphisms spanning the LTA4H gene have also been correlated with increased risk of asthma and allergy susceptibility . The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. − …”

Section: Introductionmentioning

confidence: 99%

“…31 The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. [32][33][34][35][36][37][38][39][40][41][42][43] The active site pocket of LTA4H is a 17 A ˚long L-shaped cleft capable of binding the leukotriene A4 substrate. The crystal structure of LTA4H 26 was originally solved bound to bestatin (1), a low molecular weight secondary metabolite of Streptomyces olivoreticuli 44 and a component of the FOL library.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Davies¹,

Mamat²,

et al. 2009

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We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein−protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.

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“…This data set included a total of 142 compounds of substantial chemical diversity and activity ranged from 0.5 nM to 9700 nM. The diverse nature of these compounds included the derivatives of: Kelatorphan [37][38][39][40][41][42][43].…”

Section: Collection Of Data Setmentioning

confidence: 99%

Development of Predictive Quantitative Structure–Activity Relationship Model and Its Application in the Discovery of Human Leukotriene A4 Hydrolase Inhibitors

et al. 2012

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Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase

Cited by 14 publications

References 16 publications

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Development of Predictive Quantitative Structure–Activity Relationship Model and Its Application in the Discovery of Human Leukotriene A4 Hydrolase Inhibitors

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Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase

Cited by 14 publications

References 16 publications

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A4 Hydrolyase

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A4 Hydrolyase

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Development of Predictive Quantitative Structure–Activity Relationship Model and Its Application in the Discovery of Human Leukotriene A4 Hydrolase Inhibitors

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Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase

Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A₄ Hydrolyase