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Adenosine Kinase Inhibitor

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Elizabeth A. Kowaluk – One of the best experts on this subject based on the ideXlab platform.

Michael F. Jarvis – One of the best experts on this subject based on the ideXlab platform.

  • the Adenosine Kinase Inhibitor abt 702 augments eeg slow waves in rats
    Brain Research, 2004
    Co-Authors: Richard J Radek, Michael W Decker, Michael F. Jarvis
    Abstract:

    ABT-702 is a novel and selective non-nucleoside Adenosine Kinase (AK) Inhibitor that produces increases in endogenous extracellular Adenosine. Adenosine (ADO) is thought to be an important neuromodulator of sleep, therefore, the effects of ABT-702 and AK inhibition were examined on rat EEG and sleep, and compared to ADO receptor agonists to further evaluate the role of ADO receptor activation on sleep related EEG patterns. ABT-702 (10.0–30.0 μmol/kg, i.p.) increased the amplitude of the 1–4 Hz band (Fast FourFouriernsform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 μmol/kg, i.p.), a centrally active, non-selective Adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 μmol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 μmol/kg, i.p.), a peripherally active antagonist, did not, indicating that the EEG effects of ABT-702 are mediated by a central ADO receptor mechanism. The selective A1 agonist N6-cyclopentylAdenosine (CPA, 30.0 μmol/kg, i.p.) also increased the amplitude of 1–4 Hz band, but was not as efficacious as ABT-702. In contrast, the A2A agonist CGS-21680 (1.0–10.0 μmol/kg, i.p.) and the non-selective agonist, N6-ethylcarboximidoAdenosine (NECA, 0.03–0.1 μmol/kg, ip.), lowered 1–4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 μmol/kg, i.p.) was found to significantly increase slow wave sleep and decrease REM sleep in rats implanted with both EEG and EMG electrodes for evaluation of sleep. These studies demonstrate that increased extracellular Adenosine through AK inhibition can elicit modulatory effects on EEG slow waves via an interaction with central ADO receptor subtypes.

  • analgesic and anti inflammatory effects of a 286501 a novel orally active Adenosine Kinase Inhibitor
    Pain, 2002
    Co-Authors: Michael F. Jarvis, S Mcgaraughty, J Mikusa, Marlon D Cowart, Chihhung Lee, Carol T Wismer, Chang Zhu, Katharine L Chu, Kathy L Kohlhaas, Andrew O Stewart
    Abstract:

    Abstract Adenosine (ADO) is an Inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme, Adenosine Kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK Inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. N7-((1′R,2′S,3′R,4′S)-2′,3′-dihydroxy-4′-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent ( IC 50 =0.47 nM ) carbocyclic nucleoside AK Inhibitor that has no significant activity ( IC 50 >100 μM ) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 values>10 μM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive Inhibitor with respect to ADO and non-competitive with respect to MgATP2−. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligaligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent ( ED 50 =1 μmol / kg , p.o.) to reduce carrageenan-induced inflammatory thermal hypehyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx ( ED 50 =10 μmol / kg , p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain ( ED 50 =20 μmol / kg , p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following repeated administration, A-286501 showed less potential to produce tolerance as compared to morphine. Thus, A-286501 is a structurally novel AK Inhibitor that effectively attenuates nociception by a non-opioid, non-non-steroidal anti-inflammatory drug ADO, receptor mediated mechanism.

  • discovery of 4 amino 5 3 bromophenyl 7 6 morpholino pyridin 3 yl pyrido 2 3 d pyrimidine an orally active non nucleoside Adenosine Kinase Inhibitor
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Chihhung Lee, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Michael Williams, Meiqun Jiang, Greg Gfesser, Richard J Perner, Ki H Kim, And Andrew O Stewart
    Abstract:

    Adenosine (ADO) is an endogenous homeostatic Inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC50 = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC50 = 1.7 nM) non-nucleoside AK Inhibitor with oral activity in animal models of pain and inflammation.

Chihhung Lee – One of the best experts on this subject based on the ideXlab platform.

  • crystal structures of human Adenosine Kinase Inhibitor complexes reveal two distinct binding modes
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Steven W Muchmore, Richard A Smith, Andrew O Stewart, Marlon D Cowart, Arthur Gomtsyan, Mark A Matulenko, Jean M Severin, Shripad S Bhagwat, Chihhung Lee, Elizabeth A. Kowaluk
    Abstract:

    Adenosine Kinase (AK) is an enzyme responsible for converting endogenous Adenosine (ADO) to Adenosine monophosphate (AMP) in an Adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large α/β Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed α/β domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK Inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of Inhibitors:  the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the Inhibitor classes by a 30° rotation of the small domain relative to the large domain. This change in binding mode …

  • analgesic and anti inflammatory effects of a 286501 a novel orally active Adenosine Kinase Inhibitor
    Pain, 2002
    Co-Authors: Michael F. Jarvis, S Mcgaraughty, J Mikusa, Marlon D Cowart, Chihhung Lee, Carol T Wismer, Chang Zhu, Katharine L Chu, Kathy L Kohlhaas, Andrew O Stewart
    Abstract:

    Abstract Adenosine (ADO) is an Inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme, Adenosine Kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK Inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. N7-((1′R,2′S,3′R,4′S)-2′,3′-dihydroxy-4′-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent ( IC 50 =0.47 nM ) carbocyclic nucleoside AK Inhibitor that has no significant activity ( IC 50 >100 μM ) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 values>10 μM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive Inhibitor with respect to ADO and non-competitive with respect to MgATP2−. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent ( ED 50 =1 μmol / kg , p.o.) to reduce carrageenan-induced inflammatory thermal hyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx ( ED 50 =10 μmol / kg , p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain ( ED 50 =20 μmol / kg , p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following repeated administration, A-286501 showed less potential to produce tolerance as compared to morphine. Thus, A-286501 is a structurally novel AK Inhibitor that effectively attenuates nociception by a non-opioid, non-non-steroidal anti-inflammatory drug ADO, receptor mediated mechanism.

  • discovery of 4 amino 5 3 bromophenyl 7 6 morpholino pyridin 3 yl pyrido 2 3 d pyrimidine an orally active non nucleoside Adenosine Kinase Inhibitor
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Chihhung Lee, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Michael Williams, Meiqun Jiang, Greg Gfesser, Richard J Perner, Ki H Kim, And Andrew O Stewart
    Abstract:

    Adenosine (ADO) is an endogenous homeostatic Inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC50 = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC50 = 1.7 nM) non-nucleoside AK Inhibitor with oral activity in animal models of pain and inflammation.

R. T. Smolenski – One of the best experts on this subject based on the ideXlab platform.

  • Metabolism of 4-pyridone-3-carboxamide-1-β-d-ribonucleoside (4PYR) in rodent tissues and in vivo
    Molecular and Cellular Biochemistry, 2011
    Co-Authors: P. Romaszko, E. M. Slominska, C. Orlewska, M. Lipinski, R. T. Smolenski
    Abstract:

    Our previous studies identified 4-pyridone-3-carboxamide-1-β- d –ribonucleoside (4PYR) phosphates in human erythrocytes. We demonstrated formation of these nucleotides by phosphorylation of 4PYR and potential toxicity due to disruption of erythrocyte energy balance. This study aimed to evaluate the ability of the other cell types to phosphorylate 4PYR to characterize function and toxicity of these compounds. Homogenates of rat heart, kidneys, and liver were used to study the rate of 4PYR phosphorylation in the presence of ATP. In another experiment, 4PYR was administered into mouse as repeated subcutaneous injections and into rats as intraperitoneal infusion. After 7 days, heart, liver, kidney, lungs, and skeletal muscle were collected, and the concentration of 4PYR nucleotides was evaluated. HPLC was used to measure 4PYR and 4PYR nucleotides in homogenate and specimens from in vivo experiments. 4PYR was rapidly phosphorylated by the liver homogenate (390 ± 27 nmol/min/g wet wt). Significant rates were reported in the heart and kidneys’ homogenates: 34.3 ± 4.3 nmol/min/g and 33.2 ± 9.2 nmol/min/g, respectively. Phosphorylation of 4PYR was almost completely inhibited by Adenosine Kinase Inhibitor 5′-iodotubercidin. Administration of 4PYR in vivo resulted in accumulation of 4PYR monophosphate in the liver, heart, skeletal muscle, and lung (20–220 nmol/g dry wt) except kidney (

  • metabolism of 4 pyridone 3 carboxamide 1 β d ribonucleoside 4pyr in rodent tissues and in vivo
    Molecular and Cellular Biochemistry, 2011
    Co-Authors: P. Romaszko, E. M. Slominska, C. Orlewska, M. Lipinski, R. T. Smolenski
    Abstract:

    Our previous studies identified 4-pyridone-3-carboxamide-1-β-d-ribonucleoside (4PYR) phosphates in human erythrocytes. We demonstrated formation of these nucleotides by phosphorylation of 4PYR and potential toxicity due to disruption of erythrocyte energy balance. This study aimed to evaluate the ability of the other cell types to phosphorylate 4PYR to characterize function and toxicity of these compounds. Homogenates of rat heart, kidneys, and liver were used to study the rate of 4PYR phosphorylation in the presence of ATP. In another experiment, 4PYR was administered into mouse as repeated subcutaneous injections and into rats as intraperitoneal infusion. After 7 days, heart, liver, kidney, lungs, and skeletal muscle were collected, and the concentration of 4PYR nucleotides was evaluated. HPLC was used to measure 4PYR and 4PYR nucleotides in homogenate and specimens from in vivo experiments. 4PYR was rapidly phosphorylated by the liver homogenate (390 ± 27 nmol/min/g wet wt). Significant rates were reported in the heart and kidneys’ homogenates: 34.3 ± 4.3 nmol/min/g and 33.2 ± 9.2 nmol/min/g, respectively. Phosphorylation of 4PYR was almost completely inhibited by Adenosine Kinase Inhibitor 5′-iodotubercidin. Administration of 4PYR in vivo resulted in accumulation of 4PYR monophosphate in the liver, heart, skeletal muscle, and lung (20–220 nmol/g dry wt) except kidney (<1 nmol/g). In contrast to erythrocytes, no 4PYR triphosphate formation (<1 nmol/g) was observed in any of the organs studied. We conclude that not only the erythrocytes but also other cell types are capable of phosphorylating 4PYR to form 4PYR monophosphate. Potential toxicity or physiological role of 4PYR in peripheral organs could be considered, but mechanisms will be different from that in erythrocytes.

Michael Williams – One of the best experts on this subject based on the ideXlab platform.

  • discovery of 4 amino 5 3 bromophenyl 7 6 morpholino pyridin 3 yl pyrido 2 3 d pyrimidine an orally active non nucleoside Adenosine Kinase Inhibitor
    Journal of Medicinal Chemistry, 2001
    Co-Authors: Chihhung Lee, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Michael Williams, Meiqun Jiang, Greg Gfesser, Richard J Perner, Ki H Kim, And Andrew O Stewart
    Abstract:

    Adenosine (ADO) is an endogenous homeostatic Inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC50 = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC50 = 1.7 nM) non-nucleoside AK Inhibitor with oral activity in animal models of pain and inflammation.

  • the effect of abt 702 a novel Adenosine Kinase Inhibitor on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury
    British Journal of Pharmacology, 2001
    Co-Authors: Rie Suzuki, Elizabeth A. Kowaluk, Michael F. Jarvis, Michael Williams, Louise C Stanfa, Anthony H Dickenson
    Abstract:

    Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside Adenosine Kinase (AK) Inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nervnerve injury (L5/L6 spinal nerve ligaligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. Protection of endogenous Adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous Adenosine-mediated Inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states. British Journal of Pharmacology (2001) 132, 1615–1623; doi:10.1038/sj.bjp.0703972

  • anti inflammatory effects of abt 702 a novel non nucleoside Adenosine Kinase Inhibitor in rat adjuvant arthritis
    Journal of Pharmacology and Experimental Therapeutics, 2001
    Co-Authors: David L Boyle, Elizabeth A. Kowaluk, Michael F. Jarvis, Shripad S Bhagwat, Chihhung Lee, Michael Williams, Gary S Firestein
    Abstract:

    Adenosine (ADO) is a homeostatic Inhibitory autocoid that is released at sites of inflammation and tissue injury, and exerts anti-inflammatory effects via multiple interactions at ADO receptor subtypes. Inhibition of ADO Kinase (AK) increases extracellular ADO concentrations and AK Inhibitors have demonstrated ADO-mediated anti-inflammatory effects in acute models of inflammation. To evaluate the potential utility of this approach in chronic inflinflammation, a novel, potent, and selective non-nucleoside AK Inhibitor, ABT-702, was tested in the rat adjuvant arthritis model. Animals were immunized with complete Freund‘s adjuvant on day 0 and were treated with vehicle or ABT-702 (20 mg/kg/b.i.d. p.o.) beginning on day 8. ABT-702 significantly inhibited arthritis as determined by paw volume. In addition, histologic and radiographic evidence of bone and cartilage destruction was significantly decreased in the treated group. Coadministration of the ADO receptor antagonist theophylline attenuated the anti-inflammatory effects of ABT-702, suggesting that this action was mediated through endogenous ADO release. To evaluate the mechanism of chondroprotection, Northern blot and electrophoretic mobility shift assays were performed on joints samples. These studies demonstrated that ABT-702 suppressed collagenase and stromelysin gene expression in treated animals. In addition, the activator protein-1 and nuclear factor-kappaB binding activity was also decreased. Therefore, ABT-702 inhibited clinical, radiographic, and histologic evidence of chronic inflammatory arthritis. The mechanism of joint protection is likely related to suppressed transcription factor activation and matrix metalloproteinase gene expression.