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BioAssay: AID 6765

Inhibition of 5-lipoxygenase from mouse macrophage

The investigation of the SAR of 5-lipoxygenase (5-LO) inhibition of a series of racemic (methoxyalkyl)thiazoles, exemplified by compound 7 (ZM-211965), has led to other active, racemic derivatives in which the thiazole moiety has been replaced by an ester or an ether. Furthermore, the cyclization of the ethers has given a highly potent, but achiral series, the methoxytetrahydropyrans more ..
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 Tested Compounds
 Tested Compounds
All(11)
 
 
Active(11)
 
 
 Tested Substances
 Tested Substances
All(11)
 
 
Active(11)
 
 
AID: 6765
Data Source: ChEMBL (3866)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-21
Modify Date: 2014-08-23

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Arachidonate 5-lipoxygenase; Short=5-LO; Short=5-lipoxygenase
Description ..   
Protein Family: PLAT_LOX
Comment ..   

Gene:ALOX5     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 11
Description:
Title: Conformational analysis of 5-lipoxygenase inhibitors: role of the substituents in chiral recognition and on the active conformations of the (methoxyalkyl)thiazole and methoxytetrahydropyran series.

Abstract: The investigation of the SAR of 5-lipoxygenase (5-LO) inhibition of a series of racemic (methoxyalkyl)thiazoles, exemplified by compound 7 (ZM-211965), has led to other active, racemic derivatives in which the thiazole moiety has been replaced by an ester or an ether. Furthermore, the cyclization of the ethers has given a highly potent, but achiral series, the methoxytetrahydropyrans (methoxyTHP), exemplified by 41 (ZD-2138) presently under clinical evaluation. More recent structural investigations have led to chiral members of this series bearing a 2-methyl substituent in the tetrahydropyran ring. The potential for enantioselectivity in each of the three noncyclic, racemic series led us to synthesize the pure enantiomers ((R)-13c, (S)-13c, (R)-13d, (S)-13d, (R)-15c, (S)-15c, (R)-16b, (S)-16b, and (R)-16c, (S)-16c) and to determine their absolute configuration. The biological activity of each enantiomer was evaluated in intact mouse macrophages and in human whole blood and showed that, of these three series, only the thiazole is enantioselective and that the active configuration is (S) (being between 2 and 3 orders of magnitude more potent than the (R) isomer in mouse macrophages). Conformational analysis using systematic conformational searching, molecular mechanics, and semiempirical methods has been performed on the chiral compounds, and the results have helped to explain the enantioselectivity in the thiazole series and to define the role of the substituents around the quaternary carbon. Simultaneously in the achiral tetrahydropyran (THP) series, the critical role of the methoxy substituent has been examined through the synthesis of the ethyl (24b), ester (22b), methoxymethyl ether (26), hydroxymethyl (25b), aldehyde (27b), ketone (29b), hydroxy (31b), and methyl (23b) analogues and by analysis of their biological and conformational properties. This approach, complemented by the results of a similar study carried out on the Z and E isomers of the chiral ethyl-2-methylTHP derivative (39b and 40b), has also led to the characterization of the active conformation in this series. The whole study has identified new elements to clarify the 3D structural requirements of the 5-LO active site.
(PMID: 8289184)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
Result Definitions
Show more
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatμM
10IC50 standard valueIC50 standard valueFloatnM

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
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