Synthesis of Imidazopyridines and Purines as Potent Inhibitors of Leukotriene A4 Hydrolase

Penning, Thomas D.; Chandrakumar, Nizal S.; Desai, B. N.; Djurić, Stevan W.; Gasiecki, Alan F.; Malecha, James W.; Miyashiro, Julie M.; Russell, Mark A.; Askonas, Leslie J.; Gierse, James K.; Harding, Elizabeth I.; Highkin, Maureen; Kachur, James F.; Kim, Suzanne H; Villani-Price, Doreen; Pyla, E.Yvonne; Ghoreishi-Haack, Nayereh; Smith, Walter G.

doi:10.1016/s0960-894x(03)00039-8

Cited by 28 publications

(13 citation statements)

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“…(31) The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. 32−43 …”

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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“…(31) The importance of LTA4H as a therapeutic target is exemplified by the development of multiple inhibitors representing different chemotypes. 32−43 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Davies¹,

Mamat²,

et al. 2009

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“…A different approach to attenuate the production of LTB 4 has been through the inhibition of LTA 4 H ( Haeggstrom, 2004 ). A series of inhibitors of LTA 4 H have been described with efficacy in vitro , while their anti‐inflammatory profile in vivo has also been reported, although toxicity and pharmacokinetic issues of some of those early compounds were identified ( Penning, 2001 ; Askonas et al , 2002 ; Kachur et al , 2002 ; Penning et al , 2002 , 2003 ). Recent studies have shown the activity of a novel, highly selective and orally effective LTA 4 H inhibitor, JNJ 26993135, in a number of murine inflammatory models ( Rao et al , 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A₄ hydrolase

Whittle

Varga

Berkó

et al. 2008

British J Pharmacology

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Background and purpose: Leukotriene B 4 (LTB 4 ), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A 4 hydrolase (LTA 4 H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB 4 synthesis is through the use of inhibitors of LTA 4 H, such as the novel, potent and selective compound, JNJ 26993135. Experimental approach: The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB 4 and of the pro-inflammatory cytokines, tumour necrosis factor-a (TNF-a) and interleukin-6 (IL-6) were measured. Key results: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg À1 , twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dosedependently reduced the elevated colonic levels of LTB 4 , as well as the inflammatory biomarkers, MPO, IL-6 and TNF-a. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB 4 in whole blood following oral administration. Conclusions and implications: These results with JNJ 26993135 in the rat TNBS model support the role of LTB 4 in colitis and the potential value of targeting LTA 4 H for the treatment of inflammatory bowel diseases.

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“…Among the predicted human targets, B2 bradykinin receptor, cGMP-dependent 3',5'-cyclic phosphodiesterase, Type-2 angiotensin II receptor, Phospholipase A 2 and TGF-beta receptor type-1 were found to have likelihood scores of 11.54, 9.32, 8.8, 8.14 and 8.05 respectively, which were all empirically classified as being significant. Evidently, imidazopyridines were reported as potent inhibitors for leukotriene A 4 hydrolase, a pro-inflammatory mediator implicated in the pathogenesis of a number of diseases including inflammatory bowel disease and arthritis [ 32 ].Therefore, we considered the Phospholipase A 2 as a predictive target for the novel imidazopyridines.…”

Section: Resultsmentioning

confidence: 99%

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

et al. 2015

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Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A2 (PLA2). In vitro analysis confirmed the predicted target PLA2 for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA2 with an IC50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA2.

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Synthesis of Imidazopyridines and Purines as Potent Inhibitors of Leukotriene A4 Hydrolase

Cited by 28 publications

References 9 publications

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A₄ hydrolase

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

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Synthesis of Imidazopyridines and Purines as Potent Inhibitors of Leukotriene A4 Hydrolase

Cited by 28 publications

References 9 publications

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

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Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A₄ hydrolase