d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Hin, Niyada; Duvall, Bridget; Berry, James F.; Ferraris, Dana; Rais, Rana; Alt, Jesse; Rojas, Camilo; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1016/j.bmcl.2016.02.068

Cited by 12 publications

(6 citation statements)

References 17 publications

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“…Thus, lower doses could simply take longer to reach the necessary threshold in humans. The same safety concerns also apply for the pharmacological inhibition of DAO, which is in clinical trials to increase d -serine levels [44] , [45] , [46] . Within this study, we do not provide direct evidence for a role of d -serine or d -serine elevating drugs in the regulation of insulin secretion in humans.…”

Section: Discussionmentioning

confidence: 98%

Chronic d-serine supplementation impairs insulin secretion

Suwandhi

Hausmann

Braun

et al. 2018

Molecular Metabolism

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ObjectiveThe metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis.MethodsWe apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals.ResultsWe show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans.ConclusionThus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.

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Section: Discussionmentioning

confidence: 98%

Chronic d-serine supplementation impairs insulin secretion

Suwandhi

Hausmann

Braun

et al. 2018

Molecular Metabolism

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“…In C57BL/6 mice treated with a DAO inhibitor in their drinking water for three days, D-serine levels were increased in the plasma and kidney, but not in the brain, when compared with control mice (Sershen et al, 2016 ). Co-administration of D-serine with a DAO inhibitor increased plasma D-serine levels and delayed the disappearance of D-serine from the plasma compared with D-serine administration alone (Alt et al, 2011 ; Rais et al, 2012 ; Hin et al, 2015 , 2016 ; Rojas et al, 2016 ). As well as in plasma, extracellular D-serine levels in the frontal cortex (Hashimoto et al, 2009 ) and D-serine levels in the spinal cord (Lu et al, 2012 ) were elevated in mice treated with D-serine plus a DAO inhibitor, compared with mice treated with D-serine alone.…”

Section: Physiological Substrates (Table 2 )mentioning

confidence: 99%

Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates

Koga¹,

Miyoshi²,

Sakaue³

et al. 2017

Front. Mol. Biosci.

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d-Amino-acid oxidase (DAO) catalyzes the oxidative deamination of d-amino acids. DAO is present in a wide variety of organisms and has important roles. Here, we review the distribution and physiological substrates of mouse DAO. Mouse DAO is present in the kidney, brain, and spinal cord, like DAOs in other mammals. However, in contrast to other animals, it is not present in the mouse liver. Recently, DAO has been detected in the neutrophils, retina, and small intestine in mice. To determine the physiological substrates of mouse DAO, mutant mice lacking DAO activity are helpful. As DAO has wide substrate specificity and degrades various d-amino acids, many d-amino acids accumulate in the tissues and body fluids of the mutant mice. These amino acids are d-methionine, d-alanine, d-serine, d-leucine, d-proline, d-phenylalanine, d-tyrosine, and d-citrulline. Even in wild-type mice, administration of DAO inhibitors elevates D-serine levels in the plasma and brain. Among the above d-amino acids, the main physiological substrates of mouse DAO are d-alanine and d-serine. These two d-amino acids are most abundant in the tissues and body fluids of mice. d-Alanine derives from bacteria and produces bactericidal reactive oxygen species by the action of DAO. d-Serine is synthesized by serine racemase and is present especially in the central nervous system, where it serves as a neuromodulator. DAO is responsible for the metabolism of d-serine. Since DAO has been implicated in the etiology of neuropsychiatric diseases, mouse DAO has been used as a representative model. Recent reports, however, suggest that mouse DAO is different from human DAO with respect to important properties.

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“…We introduced modifications in the linker and in the pendant aromatic part while we used acidic and acid bioisoster headgroups already described for DAAO inhibitors [11,13,14,15,16]. In the first step, we explored what kind of interactions could be formed between the flexible loop and the aromatic part of the compounds, so we have designed derivatives of compound 8 mono-substituted at the aromatic part.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biochemical Evaluation of Lid-Open d-Amino Acid Oxidase Inhibitors

et al. 2019

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Most of the known inhibitors of d-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218−224 at the top of the binding pocket. These compounds have a significantly larger size and more beneficial physicochemical properties than most reported DAAO inhibitors, however, their structure-activity relationship is poorly explored. Here we report the synthesis and evaluation of this type of DAAO inhibitors that open the lid over the active site of DAAO. In order to collect relevant SAR data we varied two distinct parts of the inhibitors. A systematic variation of the pendant aromatic substituents according to the Topliss scheme resulted in DAAO inhibitors with low nanomolar activity. The activity showed low sensitivity to the substituents investigated. The variation of the linker connecting the pendant aromatic moiety and the acidic headgroup revealed that the interactions of the linker with the enzyme were crucial for achieving significant inhibitory activity. Structures and activities were analyzed based on available X-ray structures of the complexes. Our findings might support the design of drug-like DAAO inhibitors with advantageous physicochemical properties and ADME profile.

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d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Cited by 12 publications

References 17 publications

Chronic d-serine supplementation impairs insulin secretion

Chronic d-serine supplementation impairs insulin secretion

Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates

Synthesis and Biochemical Evaluation of Lid-Open d-Amino Acid Oxidase Inhibitors

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