Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

Rashidi, Mohammad‐Reza; Pashaei-Asl, Roghiyeh

doi:10.5772/33202

Cited by 3 publications

(3 citation statements)

References 74 publications

(111 reference statements)

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“…This discrepancy prompted us to assess susceptibility of the electron deficient 5-cyanopyrimidine ring of 18 to aldehyde oxidase (AO) metabolism. Aldehyde oxidase is a molybdenum-containing cytoplasmic enzyme that catalyzes the oxidation of nitrogen-containing heterocycles . Microsomal assays utilize membrane fractions and do not capture clearance by AO .…”

Section: Results and Discussionmentioning

confidence: 99%

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

et al. 2016

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Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.

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Section: Results and Discussionmentioning

confidence: 99%

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

et al. 2016

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“…These analogs exhibited improved potency and selectivity but were poorly soluble and had high turnover in microsomes and consequently displayed poor pharmacokinetics in the rat. The observed high clearance was hypothesized to be due to action of aldehyde oxidase (AO) or xanthine oxidase (XO) on the purine ring . The similarly potent and selective pyrrolopyrimidine 11 was an attempt to blunt this activity, but 11 still suffered high microsomal clearance, much like 8 and 9 (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…The observed high clearance was hypothesized to be due to action of aldehyde oxidase (AO) or xanthine oxidase (XO) on the purine ring. 26 The similarly potent and selective pyrrolopyrimidine 11 was an attempt to blunt this activity, but 11 still suffered high microsomal clearance, much like 8 and 9 (Table 2). In spite of the low solubility and high metabolism of the ether-linked analogs 7, 8, and 11, we were interested in these compounds because of their higher selectivity; however, it became apparent that the compounds are chemically unstable, as the fragment 9H-purin-6-ol (from 7, 8) was identified in solutions after several days at neutral pH.…”

Section: Table 2 Comparison Of (S)-methyl Analogs To Des-methyl Analogsmentioning

confidence: 99%

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Cushing

Hao²,

Shin³

et al. 2014

J. Med. Chem.

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The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

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Gender-related effects on urine l-cystine metastability

et al. 2013

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Cystinuria is an autosomal recessive disease that causes L-cystine precipitation in urine and nephrolithiasis. Disease severity is highly variable; it is known, however, that cystinuria has a more severe course in males. The aim of this study was to compare L-cystine metastability in first-morning urine collected from 24 normal female and 24 normal male subjects. Samples were buffered at pH 5 and loaded with L-cystine (0.4 and 4 mM final concentration) to calculate the amount remaining in solution after overnight incubation at 4 °C; results were expressed as Z scores reflecting the L-cystine solubility in each sample. In addition, metabolomic analyses were performed to identify candidate compounds that influence L-cystine solubility. L-cystine solubility Z score was +0.44 ± 1.1 and -0.44 ± 0.70 in female and male samples, respectively (p < 0.001). Further analyses showed that the L-cystine solubility was independent from urine concentration but was significantly associated with low urinary excretion of inosine (p = 0.010), vanillylmandelic acid (VMA) (p = 0.015), adenosine (p = 0.029), and guanosine (p = 0.032). In vitro L-cystine precipitation assays confirmed that these molecules induce higher rates of L-cystine precipitation in comparison with their corresponding dideoxy molecules, used as controls. In silico computational and modeling analyses confirmed higher binding energy of these compounds. These data indicate that urinary excretion of nucleosides and VMA may represent important factors that modulate L-cystine solubility and may represent new targets for therapy in cystinuria.

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Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

Cited by 3 publications

References 74 publications

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Gender-related effects on urine l-cystine metastability

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