1,2,4-Triazolo-[1,5-<i>a</i>]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction

Ahmed, Saleh; Ayscough, Andrew; Barker, Greg R.; Canning, Hannah E.; Davenport, Richard; Downham, Robert; Harrison, David; Jenkins, Kerry; Kinsella, Natasha; Livermore, David G.; Wright, Susanne; Ivetac, Anthony; Skene, R.J.; Wilkens, Steven J.; Webster, Natalie A.; Hendrick, Alan G.

doi:10.1021/acs.jmedchem.7b00352

Cited by 31 publications

(37 citation statements)

References 47 publications

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“…Triazolo [1,5-a]azines have attracted much attention from both medical chemistry and material science communities. Thus, [1,2,4]triazolo [1,5-a]pyridine scaffold was used in design of TDP2 [1], HIF PHD-1 [2], VEGFR-2 [3] and various types of JAK kinase [4,5] inhibitors. Furthermore, triazolo [1,5-a]pyridine derivatives GLPG0634 (filgotinib) and CEP33779 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Also this heterocyclic unit was shown to be useful in design of host materials for high-performance red [6], white and RGB [7] or green [8] PhOLEDs. Similarly, [1,2,4]triazolo [1,5-a]pyrimidines, which chemistry recently was reviewed, have a broad spectrum of biological activity [9]. [1,2,4]Triazolo [1,5a]pyrazines and quinoxalines was used in design of A2A [10,11] and A3 [12,13] The practical significance of such scaffolds stimulated the development of viable synthetic methods for their preparation [9,14].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, [1,2,4]triazolo [1,5-a]pyrimidines, which chemistry recently was reviewed, have a broad spectrum of biological activity [9]. [1,2,4]Triazolo [1,5a]pyrazines and quinoxalines was used in design of A2A [10,11] and A3 [12,13] The practical significance of such scaffolds stimulated the development of viable synthetic methods for their preparation [9,14]. One of the common approaches to [1,2,4]triazolo [1,5-a]azines is an oxidative cyclization of 2-pyridyl, pyrazinyl, pyrimidyl etc., amidines or aminoguanidines to form N-N bond with various oxidants such as Pb(OAc)4 [15], PhI(OCOCF3)2 [16], iodine [17], N-Cl reagents [18,19] or electrolysis [20].…”

Section: Introductionmentioning

confidence: 99%

“…N-Aminopyridium salts readily give corresponding pyridinium-N-imines upon deprotonation. Such imines were known to react with nitriles to yield [1,2,4] [26,27]. This reaction was applied to synthesis of deuterated [28] or 2-arylsubstituted derivatives library for antifungal [29] and anticancer [30] activity screening.…”

Section: Introductionmentioning

confidence: 99%

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1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines – combined experimental and theoretical studies

Vorob’ev¹,

Borodkin²,

Andreev³

et al. 2020

Preprint

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Series of 2-pyridyl substituted [1,2,4]triazolo[1,5-a]azines have been synthesized by reaction of cyanopyridines with N-aminoazinium mesitylenesulfonates under basic conditions. The reaction proceeds smoothly with pyridinium, 1,10-phenanthrolinium and 8-oxyquinolinium salts. In case of quinolinium and isoquinolinium salts dimers of corresponding N-imines were isolated. Pyrazinium- and pyridazinium-N-imines didn’t possess any reactivity toward cyanopyridines. DFT studies give high activation barriers for 4-cyanopyridine cycloaddition to quinolinium and pyrazinium-N-imnes as well as highly negative free energy of dimerisation for quinolinium and isoquinolinium-N-imnes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines – combined experimental and theoretical studies

Vorob’ev¹,

Borodkin²,

Andreev³

et al. 2020

Preprint

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“…Crystal structure of parts of the PHD2 protein has been known for over a decade know [165][166]. While the crystal structure of PHD1 was recently described [167], PHD3 is still awaiting to be uncovered. It is known, however, from sequence comparison and modeling studies that the catalytically active Cterminus is highly conserved throughout all isoforms [166].…”

Section: Phd Inhibitors: Moving Away From Pan-phd Inhibitionmentioning

confidence: 99%

Oxygen Sensors in Atherosclerosis

Demandt¹

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Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat

et al. 2021

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Human prolyl‐hydroxylases (PHDs) are hypoxia‐sensing 2‐oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia‐inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia‐related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late‐stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain‐penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active‐site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π‐π‐stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2–β3, which are involved in dynamic substrate binding/product release.

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1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction

Cited by 31 publications

References 47 publications

1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines – combined experimental and theoretical studies

1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines – combined experimental and theoretical studies

Oxygen Sensors in Atherosclerosis

Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat

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