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Detlev Boison - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Kinase expression determines dna methylation in cancer cell lines
The FASEB Journal, 2021Co-Authors: Amir E Wahba, Hoda M Gebril, Denise Fedele, Enmar Alharfoush, Kiran S Toti, Kenneth Jacobson, Detlev BoisonAbstract:DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms Adenosine. We hypothesized that an Adenosine Kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC50 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.
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Adenosine Kinase inhibition promotes proliferation of neural stem cells after traumatic brain injury
Brain communications, 2020Co-Authors: Hoda M Gebril, Rizelle Mae Rose, Raey Gesese, Martine P Emond, Yuqing Huo, Eleonora Aronica, Detlev BoisonAbstract:Traumatic brain injury (TBI) is a major public health concern and remains a leading cause of disability and socio-economic burden. To date, there is no proven therapy that promotes brain repair following an injury to the brain. In this study, we explored the role of an isoform of Adenosine Kinase expressed in the cell nucleus (ADK-L) as a potential regulator of neural stem cell proliferation in the brain. The rationale for this hypothesis is based on coordinated expression changes of ADK-L during foetal and postnatal murine and human brain development indicating a role in the regulation of cell proliferation and plasticity in the brain. We first tested whether the genetic disruption of ADK-L would increase neural stem cell proliferation after TBI. Three days after TBI, modelled by a controlled cortical impact, transgenic mice, which lack ADK-L (ADKΔneuron) in the dentate gyrus (DG) showed a significant increase in neural stem cell proliferation as evidenced by significant increases in doublecortin and Ki67-positive cells, whereas animals with transgenic overexpression of ADK-L in dorsal forebrain neurons (ADK-Ltg) showed an opposite effect of attenuated neural stem cell proliferation. Next, we translated those findings into a pharmacological approach to augment neural stem cell proliferation in the injured brain. Wild-type C57BL/6 mice were treated with the small molecule Adenosine Kinase inhibitor 5-iodotubercidin for 3 days after the induction of TBI. We demonstrate significantly enhanced neural stem cell proliferation in the DG of 5-iodotubercidin-treated mice compared to vehicle-treated injured animals. To rule out the possibility that blockade of ADK-L has any effects in non-injured animals, we quantified baseline neural stem cell proliferation in ADKΔneuron mice, which was not altered, whereas baseline neural stem cell proliferation in ADK-Ltg mice was enhanced. Together these findings demonstrate a novel function of ADK-L involved in the regulation of neural stem cell proliferation after TBI.
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transient use of a systemic Adenosine Kinase inhibitor attenuates epilepsy development in mice
Epilepsia, 2019Co-Authors: Ursula S Sandau, Mayadah Yahya, Ryan Bigej, Joseph L Friedman, Bounmy Saleumvong, Detlev BoisonAbstract:Objective Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct histopathologic and biochemical changes, which include astrogliosis and increased expression of the Adenosine-metabolizing enzyme Adenosine Kinase (ADK; EC 2.7.1.20). Increased expression of ADK contributes to epileptogenesis and is therefore a target for therapeutic intervention. We tested the prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy. Methods We used the intrahippocampal kainic acid (KA) mouse model of temporal lobe epilepsy, which is characterized by ipsilateral hippocampal sclerosis with granule cell dispersion and the development of recurrent hippocampal paroxysmal discharges (HPDs). KA-injected mice were treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 1.6 mg/kg, b.i.d., i.p.) during the latent phase of epileptogenesis from day 3-8 after injury; the period when gradual increases in hippocampal ADK expression begin to manifest. HPDs were assessed at 6 and 9 weeks after KA administration followed by epilepsy histopathology including assessment of granule cell dispersion, astrogliosis, and ADK expression. Results 5-ITU significantly reduced the percent time in seizures by at least 80% in 56% of mice at 6 weeks post-KA. This reduction in seizure activity was maintained in 40% of 5-ITU-treated mice at 9 weeks. 5-ITU also suppressed granule cell dispersion and prevented maladaptive ADK increases in these protected mice. Significance Our results show that the transient use of a small-molecule ADK inhibitor, given during the early stages of epileptogenesis, has antiepileptogenic disease-modifying properties, which provides the rationale for further investigation into the development of a novel class of antiepileptogenic ADK inhibitors with increased efficacy for epilepsy prevention.
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south s and north n methanocarba 7 deazaAdenosine analogues as inhibitors of human Adenosine Kinase
Journal of Medicinal Chemistry, 2016Co-Authors: Kiran S Toti, Detlev Boison, Antonella Ciancetta, Danielle M Osborne, Kenneth A. JacobsonAbstract:Adenosine Kinase (AdK) inhibitors raise endogenous Adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5′-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5′-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ∼ 100 nM), while the 5′-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5′-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in t...
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South (S)- and North (N)-Methanocarba-7-DeazaAdenosine Analogues as Inhibitors of Human Adenosine Kinase
2016Co-Authors: Kiran S. Toti, Detlev Boison, Danielle Osborne, Antonella Ciancetta, Kenneth A. JacobsonAbstract:Adenosine Kinase (AdK) inhibitors raise endogenous Adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5′-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5′-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ∼ 100 nM), while the 5′-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5′-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy
Michael F. Jarvis - One of the best experts on this subject based on the ideXlab platform.
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the Adenosine Kinase inhibitor abt 702 augments eeg slow waves in rats
Brain Research, 2004Co-Authors: Richard J Radek, Michael W Decker, Michael F. JarvisAbstract: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 Fourier Transform (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.
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Synthesis and biological evaluation of pteridine and pyrazolopyrimidine based Adenosine Kinase inhibitors.
Bioorganic & medicinal chemistry letters, 2004Co-Authors: Arthur Gomtsyan, Stanley Didomenico, Lee Chih-hung, Andrew O. Stewart, Shripad S. Bhagwat, Elizabeth A. Kowaluk, Michael F. JarvisAbstract:Abstract Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside Adenosine Kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.
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synthesis and structure activity relationships of 5 heteroatom substituted pyridopyrimidines as Adenosine Kinase inhibitors
ChemInform, 2003Co-Authors: Greg Gfesser, Arthur Gomtsyan, Stanley Didomenico, Andrew O. Stewart, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Chihhung Lee, Erol K Bayburt, Shripad S. BhagwatAbstract:Under stressful conditions, many cells release Adenosine to minimize tissue damage. Inhibition of intracellular Adenosine Kinase (AK) increases the local extracellular concentration of Adenosine and its effect on traumatized tissue. The synthesis and SAR of a new series of pyridopyrimidines for the inhibition of AK are described. It was found that a range of analogs with position five substituted by an amine or ether functionality increased aqueous solubility while retaining the in vitro potency of initial leads. A narrower range of analogs was active in vivo in a rat inflammatory hyperalgesia model.
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design synthesis and structure activity relationship of 6 alkynylpyrimidines as potent Adenosine Kinase inhibitors
Journal of Medicinal Chemistry, 2002Co-Authors: Arthur Gomtsyan, Stanley Didomenico, Elizabeth A. Kowaluk, J Mikusa, Mark A Matulenko, Chihhung Lee, Carol T Wismer, Kathy L Kohlhaas, Ki H Kim, Michael F. JarvisAbstract:Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
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analgesic and anti inflammatory effects of a 286501 a novel orally active Adenosine Kinase inhibitor
Pain, 2002Co-Authors: Michael F. Jarvis, J Mikusa, S Mcgaraughty, Marlon D Cowart, Chihhung Lee, Carol T Wismer, Chang Zhu, Katharine L Chu, Kathy L Kohlhaas, Andrew O. StewartAbstract: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.
Elizabeth A. Kowaluk - One of the best experts on this subject based on the ideXlab platform.
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crystal structures of human Adenosine Kinase inhibitor complexes reveal two distinct binding modes
Journal of Medicinal Chemistry, 2006Co-Authors: Steven W Muchmore, Arthur Gomtsyan, Andrew O. Stewart, Shripad S. Bhagwat, Richard A Smith, Marlon D Cowart, Mark A Matulenko, Jean M Severin, Chihhung Lee, Elizabeth A. KowalukAbstract: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 ...
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Synthesis and biological evaluation of pteridine and pyrazolopyrimidine based Adenosine Kinase inhibitors.
Bioorganic & medicinal chemistry letters, 2004Co-Authors: Arthur Gomtsyan, Stanley Didomenico, Lee Chih-hung, Andrew O. Stewart, Shripad S. Bhagwat, Elizabeth A. Kowaluk, Michael F. JarvisAbstract:Abstract Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside Adenosine Kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.
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synthesis and structure activity relationships of 5 heteroatom substituted pyridopyrimidines as Adenosine Kinase inhibitors
ChemInform, 2003Co-Authors: Greg Gfesser, Arthur Gomtsyan, Stanley Didomenico, Andrew O. Stewart, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Chihhung Lee, Erol K Bayburt, Shripad S. BhagwatAbstract:Under stressful conditions, many cells release Adenosine to minimize tissue damage. Inhibition of intracellular Adenosine Kinase (AK) increases the local extracellular concentration of Adenosine and its effect on traumatized tissue. The synthesis and SAR of a new series of pyridopyrimidines for the inhibition of AK are described. It was found that a range of analogs with position five substituted by an amine or ether functionality increased aqueous solubility while retaining the in vitro potency of initial leads. A narrower range of analogs was active in vivo in a rat inflammatory hyperalgesia model.
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design synthesis and structure activity relationship of 6 alkynylpyrimidines as potent Adenosine Kinase inhibitors
Journal of Medicinal Chemistry, 2002Co-Authors: Arthur Gomtsyan, Stanley Didomenico, Elizabeth A. Kowaluk, J Mikusa, Mark A Matulenko, Chihhung Lee, Carol T Wismer, Kathy L Kohlhaas, Ki H Kim, Michael F. JarvisAbstract:Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
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A-134974: a novel Adenosine Kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats.
Brain research, 2001Co-Authors: C Z Zhu, Elizabeth A. Kowaluk, J Mikusa, K L Chu, M Cowart, M F Jarvis, S McgaraughtyAbstract:Extracellular levels of Adenosine (ADO) can be raised through inhibition of Adenosine Kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A-134974 (IC(50)=60 pM), in a rat model of neuropathic pain (ligations of the L5/L6 spinal nerves) and explored the relative contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia (ED(50)=5 micromol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test of motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 micromol/kg, i.p.). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50)=10 nmol) in relieving tactile allodynia than delivering the compound by intracerebroventricular (ED(50)>100 nmol, i.c.v.) or intraplantar (ED(50)>500 nmol) routes suggesting that spinal sites of action are the primary contributors to the anti-allodynic action of A-134974. The anti-allodynic effects of systemic A-134974 (10 micromol/kg, i.p.) were antagonized by the non-selective ADO receptor antagonist, theophylline (30-500 nmol) administered i.t. These data demonstrate that the novel AK inhibitor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be useful as analgesic agents in a broad spectrum of pain states.
Chihhung Lee - One of the best experts on this subject based on the ideXlab platform.
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4 amino 5 aryl 6 arylethynylpyrimidines structure activity relationships of non nucleoside Adenosine Kinase inhibitors
Bioorganic & Medicinal Chemistry, 2007Co-Authors: Mark A Matulenko, Arthur Gomtsyan, Stanley Didomenico, Andrew O. Stewart, Chihhung Lee, Kathy L Kohlhaas, Meiqun Jiang, Ernest S Paight, Robin R Frey, Karen M AlexanderAbstract:A series of non-nucleoside Adenosine Kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and Adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to Adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
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crystal structures of human Adenosine Kinase inhibitor complexes reveal two distinct binding modes
Journal of Medicinal Chemistry, 2006Co-Authors: Steven W Muchmore, Arthur Gomtsyan, Andrew O. Stewart, Shripad S. Bhagwat, Richard A Smith, Marlon D Cowart, Mark A Matulenko, Jean M Severin, Chihhung Lee, Elizabeth A. KowalukAbstract: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 ...
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synthesis and structure activity relationships of 5 heteroatom substituted pyridopyrimidines as Adenosine Kinase inhibitors
ChemInform, 2003Co-Authors: Greg Gfesser, Arthur Gomtsyan, Stanley Didomenico, Andrew O. Stewart, Elizabeth A. Kowaluk, Michael F. Jarvis, Marlon D Cowart, Chihhung Lee, Erol K Bayburt, Shripad S. BhagwatAbstract:Under stressful conditions, many cells release Adenosine to minimize tissue damage. Inhibition of intracellular Adenosine Kinase (AK) increases the local extracellular concentration of Adenosine and its effect on traumatized tissue. The synthesis and SAR of a new series of pyridopyrimidines for the inhibition of AK are described. It was found that a range of analogs with position five substituted by an amine or ether functionality increased aqueous solubility while retaining the in vitro potency of initial leads. A narrower range of analogs was active in vivo in a rat inflammatory hyperalgesia model.
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design synthesis and structure activity relationship of 6 alkynylpyrimidines as potent Adenosine Kinase inhibitors
Journal of Medicinal Chemistry, 2002Co-Authors: Arthur Gomtsyan, Stanley Didomenico, Elizabeth A. Kowaluk, J Mikusa, Mark A Matulenko, Chihhung Lee, Carol T Wismer, Kathy L Kohlhaas, Ki H Kim, Michael F. JarvisAbstract:Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of Adenosine Kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
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analgesic and anti inflammatory effects of a 286501 a novel orally active Adenosine Kinase inhibitor
Pain, 2002Co-Authors: Michael F. Jarvis, J Mikusa, S Mcgaraughty, Marlon D Cowart, Chihhung Lee, Carol T Wismer, Chang Zhu, Katharine L Chu, Kathy L Kohlhaas, Andrew O. StewartAbstract: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.
Mark D Erion - One of the best experts on this subject based on the ideXlab platform.
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Adenosine Kinase inhibitors 6 synthesis water solubility and antinociceptive activity of 5 phenyl 7 5 deoxy β d ribofuranosyl pyrrolo 2 3 d pyrimidines substituted at c4 with glycinamides and related compounds
Journal of Medicinal Chemistry, 2005Co-Authors: Brett C. Bookser, Bheemarao G Ugarkar, James B Wiesner, Michael C. Matelich, Robert H Lemus, Matthew Allan, Megumi Tsuchiya, Masami Nakane, Atsushi Nagahisa, Mark D ErionAbstract:4-(Phenylamino)-5-phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (1) and related compounds known as “diaryltubercidin” analogues are potent inhibitors of Adenosine Kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50 = 6.4 mg/kg). However, the utility of this compound class is limited by poor water solubility that can be attributed to the high energy of crystallization caused by stacking of the parallel C4 and C5 aryl rings in the solid state (compound 1 and GP3269 each with pH 7.4 solubility <0.05 μg/mL). To increase water solubility, the hydrophobic C4-phenylamino substituent was replaced with a more hydrophilic group, glycinamide. This modification resulted in improved water solubility while retaining AK inhibition potency. Analogues were studied where changes in the glycinamide moiety were combined with changes to the base and sugar. A lead compound, 4-N-(N-cyclopropylcarbamoylmethyl)amino-5-phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo...
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Adenosine Kinase inhibitors 3 synthesis sar and antiinflammatory activity of a series of l lyxofuranosyl nucleosides
Journal of Medicinal Chemistry, 2003Co-Authors: Bheemarao G Ugarkar, Angelo J Castellino, M Ramirezweinhouse, Jay S Dare, Joseph J Kopcho, And Sanna Rosengren, Mark D ErionAbstract:Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that Adenosine Kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-α production, neutrophil accumulation, and edema formation. Although Adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of Adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5‘-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH2OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs bas...
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Adenosine Kinase inhibitors 1 synthesis enzyme inhibition and antiseizure activity of 5 iodotubercidin analogues
Journal of Medicinal Chemistry, 2000Co-Authors: Bheemarao G Ugarkar, Jay Dare, Angelo J Castellino, James B Wiesner, Joseph J Kopcho, And Juergen M Schanzer, Mark D ErionAbstract:In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent Adenosine Kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5‘-amino-5‘-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 μM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected α-ribofuranosyl chlorides using a phase-transfer cat...
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structure of human Adenosine Kinase at 1 5 a resolution
Biochemistry, 1998Co-Authors: Irimpan I Mathews, Mark D Erion, Steven E EalickAbstract:Adenosine Kinase (AK) is a key enzyme in the regulation of extracellular Adenosine and intracellular adenylate levels. Inhibitors of Adenosine Kinase elevate Adenosine to levels that activate nearby Adenosine receptors and produce a wide variety of therapeutically beneficial activities. Accordingly, AK is a promising target for new analgesic, neuroprotective, and cardioprotective agents. We determined the structure of human Adenosine Kinase by X-ray crystallography using MAD phasing techniques and refined the structure to 1.5 A resolution. The enzyme structure consisted of one large α/β domain with nine β-strands, eight α-helices, and one small α/β-domain with five β-strands and two α-helices. The active site is formed along the edge of the β-sheet in the large domain while the small domain acts as a lid to cover the upper face of the active site. The overall structure is similar to the recently reported structure of riboKinase from Escherichia coli [Sigrell et al. (1998) Structure 6, 183−193]. The struct...
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design synthesis and anticonvulsant activity of the potent Adenosine Kinase inhibitor gp3269
Nucleosides Nucleotides & Nucleic Acids, 1997Co-Authors: Mark D Erion, Jay Dare, Bheemarao G Ugarkar, Angelo J Castellino, James M Fujitaki, Ross Dixon, James R Appleman, James B WiesnerAbstract:Abstract The pyrrolopyrimidine nucleoside GP3269 (12) was shown to be a potent and selective inhibitor of human Adenosine Kinase (IC50 = 11 nM) and to exhibit anticonvulsant activity in rats after oral administration. Synthesis of GP3269 was accomplished in 4 steps from 4-chloro-5-iodopyrrolopyrimidine (9) and the protected 5-deoxy-1-α-chlororibose (8) using a base-catalyzed nucleoside coupling reaction and the Suzuki reaction to replace the 5-iodo substituent with phenyl.