Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors

Warshakoon, Namal C.; Wu, Shengde; Boyer, Angelique; Kawamoto, Richard M.; Renock, Sean; Xu, Kevin; Pokross, Matthew; Evdokimov, A.G.; Zhou, Su; Winter, Carol L; Walter, R.L.; Mekel, Marlene

doi:10.1016/j.bmcl.2006.08.017

Cited by 75 publications

(57 citation statements)

References 13 publications

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“…PHIs have been the subject of various recent studies [23,24], and the product ion spectrum of 2 derived from the protonated molecule [M ϩ H] ϩ at m/z 281 is depicted in Figure 1a. Upon weak collisional activation (normalized collision energy ϭ 15 arbitrary units, Xcalibur Software version 2.0; Thermo, San Jose, CA), the precursor ion consecutively eliminates water (Ϫ18 u) and carbon monoxide (Ϫ28 u) yielding the product ions at m/z 263 and 235, respectively.…”

Section: Electrospray Ionization-tandem Mass Spectrometrymentioning

confidence: 99%

“…Derivatives of 2-oxoglutarate [18,19], hydroxyanthraquinones [20], 5-acyl sulfonamides [21], dihydroxybenzoates [22], hydroxyquinolines [23], pyrazolopyridines [24], and many other compounds [25][26][27][28] were prepared and studied. One of the most promising class of candidates, which currently undergoes Phase II clinical trials [29], comprises an isoquinoline core with a 3-positioned carboxyl residue that was converted into its amide using glycine (Scheme 1-1).…”

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confidence: 99%

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Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation

Thevis

Kohler

Schlörer

et al. 2008

J. Am. Soc. Mass Spectrom.

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Within the mass spectrometric study of bisubstituted isoquinolines that possess great potential as prolylhydroxylase inhibitor drug candidates (e.g., FG-2216), unusually favored gas-phase formations of carboxylic acids after collisional activation were observed. The protonated molecule of [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid was dissociated, yielding the 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid methyleneamide cation. Subsequent dissociation caused the nominal elimination of 11 u that resulted from the loss of HCN and concomitant addition of oxygen to the product ion, which formed the protonated 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid. The preference of this structure under mass spectrometric conditions was substantiated by tandem mass spectrometry analyses using the corresponding methyl ester (1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester) that eliminated methylene (Ϫ14 u) upon collisional activation. Moreover, the major product ion of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, which resulted from the loss of water in MS 3 experiments, restored the precursor ion structure by re-addition of H 2 O. Evidences for these phenomena were obtained by chemical synthesis of proposed gas-phase intermediates, H/D exchange experiments, high-resolution/high accuracy mass spectrometry at MS n level, and "ping-pong" analyses (MS 7 , in which the precursor ion was dissociated and the respective product ion isolated to regenerate the precursor ion for repeated dissociation. Based on these results, dissociation pathways for [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid were suggested that can be further utilized for the characterization of structurally related compounds or metabolic products in clinical, forensic, or doping control analysis. (J Am Soc Mass Spectrom 2008, 19, 151-158) © 2008 American Society for Mass Spectrometry P rolyl hydroxylases have been subject of various studies because of their importance in several biochemical pathways and, thus, related diseases in case of impaired activity. Proline hydroxylation was identified as a key factor in the biosynthesis and maturation of collagen [1,2], which requires 4-hydroxylation of specific proline residues (in X-Pro-Gly motifs) to establish the characteristic triple-helical structure. However, during life-threatening fibrotic states, inappropriately large amounts of collagen are produced, and the inhibition of proline hydroxylation is desired to divert the collagen biosynthesis into a degradative pathway [3]. More recently, the catalytic role of prolyl hydroxylase isoforms in modifying conserved prolines of two oxygen-dependent degradation domains in the hypoxia-inducible factor (HIF)-1␣ was identified [4 -6]. The members of the 2-oxoglutarate-dependent dioxygenase superfamily enable the hydroxylation of the proline residues 402 and 564 of HIF-1␣ and promote its degradation via ubiquitylation and subsequent proteasomal destruction [7][8][9]. As a consequence, the presence of HIF-1...

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Section: Electrospray Ionization-tandem Mass Spectrometrymentioning

confidence: 99%

mentioning

confidence: 99%

Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation

Thevis

Kohler

Schlörer

et al. 2008

J. Am. Soc. Mass Spectrom.

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“…8,9 Because of their key role in the regulation of HIF levels, inhibition of PHD enzymes is an attractive strategy by which to potentiate the transcriptional activity of HIF in a therapeutically relevant manner. Indeed, during the last several years, intense efforts to discover PHD inhibitors have been adumbrated primarily in the patent literature, 10 and to a much lesser degree in the peer-reviewed literature, [11][12][13][14][15][16][17][18][19] leading to four compounds entering clinical trials. 20,21 In this letter, we report our efforts in this area, which led to the discovery of novel PHD inhibitors that are potent, orally active erythropoietin secretagogues.…”

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confidence: 99%

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

Rosen

Venkatesan

Peltier

et al. 2010

ACS Med. Chem. Lett.

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“…Pyrazolopyridines have a number of pharmacological properties such as antimicrobial [1,2], antidiabetes [3], anti-herpesviruses [4], anti-leishmania [5], HIF-1 prolyl hydroxylase inhibitors [6], kinase inhibitors [7], and dopaminergic properties [8]. A rapid and experimentally simple synthesis of pyrazolopyridines under mild conditions is in high demand.…”

Section: Introductionmentioning

confidence: 99%

“…Experimental section 2.1. Chemicals and apparatus 1 H NMR and 13 C NMR spectra were recorded on Bruker Avance-400 MHz spectrometer using DMSOd 6 as solvent. The elemental analyses (C, H, and N) were obtained from a Carlo ERBA Model EA 1108 analyzer.…”

Section: Introductionmentioning

confidence: 99%

A Flexible one-pot synthesis of pyrazolopyridines catalyzed by Fe3O4@SiO2-SO3H nanocatalyst under microwave irradiation

Safaei‐Ghomi

Shahbazi‐Alavi

2017

Scientia Iranica

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Abstract. Fe3O4@SiO2-SO3H nanocatalyst has been used as an e cient catalyst for the preparation of pyrazolopyridines by a multi-component reaction of ethyl acetoacetate, aldehyde, hydrazine hydrate, and ammonium acetate under microwave irradiation. Atom economy, wide range of products, excellent yields in short times, use of microwave as green method, reusability of the catalyst, and little catalyst loading are some of the important features of this protocol.

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Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors

Cited by 75 publications

References 13 publications

Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation

Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

A Flexible one-pot synthesis of pyrazolopyridines catalyzed by Fe3O4@SiO2-SO3H nanocatalyst under microwave irradiation

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