The Experts below are selected from a list of 1089 Experts worldwide ranked by ideXlab platform
Gunda I. Georg - One of the best experts on this subject based on the ideXlab platform.
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potent pyrimidine and Pyrrolopyrimidine inhibitors of testis specific serine threonine kinase 2 tssk2
ChemMedChem, 2017Co-Authors: Jon E. Hawkinson, Rondedrick Sinville, Deepti Mudaliar, Jagathpala Shetty, Tim Ward, John C. Herr, Gunda I. GeorgAbstract:Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a Pyrrolopyrimidine or pyrimidine core. The Pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these Pyrrolopyrimidine and pyrimidine scaffolds.
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Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2).
ChemMedChem, 2017Co-Authors: Jon E. Hawkinson, Rondedrick Sinville, Deepti Mudaliar, Jagathpala Shetty, Tim Ward, John C. Herr, Gunda I. GeorgAbstract:Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a Pyrrolopyrimidine or pyrimidine core. The Pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these Pyrrolopyrimidine and pyrimidine scaffolds.
D A Butterfield - One of the best experts on this subject based on the ideXlab platform.
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The Pyrrolopyrimidine U101033E is a potent free radical scavenger and prevents Fe(II)-induced lipid peroxidation in synaptosomal membranes.
Biochimica et biophysica acta, 2000Co-Authors: C M Lauderback, A M Breier, J Hackett, S Varadarajan, J Goodlett-mercer, D A ButterfieldAbstract:The Pyrrolopyrimidine U101033E is a therapeutic compound potentially useful in stroke, head injury and other oxidative stress conditions. Electron paramagnetic resonance (EPR) techniques of spin labeling and spin trapping in conjunction with measures of lipid and protein oxidation have been used to investigate the proposed antioxidant capacity of U101033E. We report potent antioxidant activity of this agent in aqueous cell-free solution as measured by spin trapping. U101033E significantly (P
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The Pyrrolopyrimidine U101033E is a potent free radical scavenger and prevents Fe(II)-induced lipid peroxidation in synaptosomal membranes
Biochimica et Biophysica Acta, 2000Co-Authors: C M Lauderback, A M Breier, S Varadarajan, J Goodlett-mercer, Janna M. Hackett, D A ButterfieldAbstract:Abstract The Pyrrolopyrimidine U101033E is a therapeutic compound potentially useful in stroke, head injury and other oxidative stress conditions. Electron paramagnetic resonance (EPR) techniques of spin labeling and spin trapping in conjunction with measures of lipid and protein oxidation have been used to investigate the proposed antioxidant capacity of U101033E. We report potent antioxidant activity of this agent in aqueous cell-free solution as measured by spin trapping. U101033E significantly ( P N - t -butyl-α-phenylnitrone (PBN)-radical adduct by 17.1% at a concentration of 1 μM, four orders of magnitude less than the concentration of PBN. As measured by the decrease in signal intensity of lipid-resident nitroxide stearate spin probes, an EPR assay for lipid peroxidation, this Pyrrolopyrimidine compound efficiently protected against hydroxyl radical-induced lipid peroxidation in cortical synaptosomal membranes deep within the membrane bilayer, but not closer to the membrane surface. In addition, U101033E partially prevents synaptosomal protein oxidation in the presence of Fe(II); however, U101033E demonstrates some protein oxidative effects itself. These results are supportive of the proposed role of U101033E as a lipid-specific antioxidant, especially for protection against lipid peroxidation that occurs deep within the membrane bilayer, but raise some potential concerns about the oxidative nature of this agent toward proteins.
Jon E. Hawkinson - One of the best experts on this subject based on the ideXlab platform.
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potent pyrimidine and Pyrrolopyrimidine inhibitors of testis specific serine threonine kinase 2 tssk2
ChemMedChem, 2017Co-Authors: Jon E. Hawkinson, Rondedrick Sinville, Deepti Mudaliar, Jagathpala Shetty, Tim Ward, John C. Herr, Gunda I. GeorgAbstract:Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a Pyrrolopyrimidine or pyrimidine core. The Pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these Pyrrolopyrimidine and pyrimidine scaffolds.
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Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2).
ChemMedChem, 2017Co-Authors: Jon E. Hawkinson, Rondedrick Sinville, Deepti Mudaliar, Jagathpala Shetty, Tim Ward, John C. Herr, Gunda I. GeorgAbstract:Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a Pyrrolopyrimidine or pyrimidine core. The Pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these Pyrrolopyrimidine and pyrimidine scaffolds.
Edward D. Hall - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective effects of the novel brain-penetrating Pyrrolopyrimidine antioxidants U-101033E and U-104067F against post-ischemic degeneration of nigrostriatal neurons.
Journal of neuroscience research, 1997Co-Authors: Paula K. Andrus, Timothy J. Fleck, Jo A. Oostveen, Edward D. HallAbstract:A 10-min period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers a delayed retrograde degeneration of 35-40% of dopaminergic nigrostriatal (NS) neurons. The mechanism of the NS degeneration is believed to involve oxygen radical formation secondary to a postischemic increase in dopamine turnover (monoamine oxidase, MAO). If the oxygen radical increase is sufficiently severe, lipid peroxidative injury to the striatal NS terminals is followed by retrograde degeneration of the NS cell bodies. In the present study, we examined whether the novel brain-penetrating lipid antioxidant Pyrrolopyrimidine, U-101033E, and its aromatized analog, U-104067F, could attenuate dopaminergic neurodegeneration in this model. Male Mongolian gerbils were dosed with U-101033E (1.5, 5, or 15 mg/kg, by mouth, twice daily) or U-104067F (5 or 15 mg/kg, by mouth, twice daily) for 27 days beginning on the day of the 10-min ischemic insult. Preservation of NS neurons was assessed by tyrosine hydroxylase immunohistochemistry at 28 days. In vehicle (40% hydroxypropyl-beta-cyclodextrin)-treated animals, there was a 42% loss of NS neurons. In contrast, gerbils that received 5 or 15 mg/kg U-101033E twice daily had only a 23% or 28% loss of NS neurons, respectively (P < 0.002 vs. vehicle). U-104067F showed little effect at sparing neurons at the 10 mg/kg dose, but did significantly attenuate neuronal loss to only 20% at the 30 mg/kg dose (P < 0.01 vs. vehicle). The results show that both the Pyrrolopyrimidines (U-101033E and U-104067F) significantly attenuate the postischemic loss of NS dopaminergic neurons and further support the involvement of a dopamine metabolism-derived, oxygen radical-induced lipid peroxidative mechanism.
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Pyrrolopyrimidines: Novel Brain-Penetrating Antioxidants with Neuroprotective Activity in Brain Injury and Ischemia Models
The Journal of pharmacology and experimental therapeutics, 1997Co-Authors: Edward D. Hall, Paula K. Andrus, S. L. Smith, T. J. Fleck, H. M. Scherch, Barry S. Lutzke, Geri A. Sawada, John S. Althaus, Philip F. Vonvoigtlander, Guy E. PadburyAbstract:A novel group of antioxidant compounds, the Pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56–70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many Pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.
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Neuroprotective Effects of the Pyrrolopyrimidine U-104067F in 3-Acetylpyridine-Treated Rats
Experimental neurology, 1996Co-Authors: Vimala H. Sethy, Jo A. Oostveen, Edward D. HallAbstract:Abstract The neuroprotective effects of U-104067F [(9-(2-morpholinyl)ethyl)2,4-di-l-pyrrolidinyl-9H-pyrimidino(4,5-b)indole monohydrochloride hydrate], a Pyrrolopyrimidine antioxidant, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. A significant (P
Naoki Teno - One of the best experts on this subject based on the ideXlab platform.
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Novel type of plasmin inhibitors: providing insight into P4 moiety and alternative scaffold to Pyrrolopyrimidine.
Bioorganic & medicinal chemistry, 2015Co-Authors: Naoki Teno, Keigo Gohda, Keiko Wanaka, Yuko Tsuda, Tadamune Otsubo, Maiko Akagawa, Eriko Akiduki, Mitsuhito Araki, Arisa Masuda, Yukiko YamashitaAbstract:Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to Pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin.
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Pyrrolopyrimidine inhibitors with hydantoin moiety as spacer can explore p4 s4 interaction on plasmin
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Naoki Teno, Keigo Gohda, Keiko Wanaka, Yuko Tsuda, Takuya Sueda, Yukiko Yamashita, Tadamune OtsuboAbstract:In the development of plasmin inhibitors, a novel chemotype, Pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer.
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Pyrrolopyrimidine-inhibitors with hydantoin moiety as spacer can explore P4/S4 interaction on plasmin.
Bioorganic & medicinal chemistry, 2014Co-Authors: Naoki Teno, Keigo Gohda, Keiko Wanaka, Yuko Tsuda, Takuya Sueda, Yukiko Yamashita, Tadamune OtsuboAbstract:In the development of plasmin inhibitors, a novel chemotype, Pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer.
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Orally bioavailable cathepsin K inhibitors with Pyrrolopyrimidine scaffold.
Current topics in medicinal chemistry, 2010Co-Authors: Naoki Teno, Keiichi MasuyaAbstract:The recent emergence of osteoporosis as a major health threat in people of advanced age has intensified the search for novel and effective pharmacologic treatments. Given that bone resorption is exceeding bone formation, a reduction in bone mass leads to disease conditions including post-menopausal osteoporosis and tumor-induced osteolysis. Our efforts in this area have focused on the optimization of non-peptidic cathepsin K inhibitors for affinity and selectivity, from an heteroaromatic nitrile as a novel scaffold. This approach has resulted in the discovery of the potent and selective cathepsin K inhibitor, 44. The concentration of cathepsin K inhibitors, including compound 44, in the target tissues such as bone marrow cavity, were predictive parameters for antibone resorptive efficacy in vivo in the rat. The high level of distribution to the bone marrow was also observed for compounds containing Pyrrolopyrimidines with novel spiro-structures as the P3 moiety. In a monkey study with the representative inhibitor 44, the antibone resorptive efficacy was detected 8 h after the compound administration. The efficacy persisted throughout the repeated treatment period of 14 days without any evidence for the development of tolerance. This article constitutes a near comprehensive review of the published scientific literature on small molecule non-peptidic inhibitors for cathepsin K developed by Novartis.
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Effect of cathepsin K inhibitors on bone resorption.
Journal of medicinal chemistry, 2008Co-Authors: Naoki Teno, Osamu Irie, Naoko Matsuura, Keiichi Masuya, Takeru Ehara, Yuko Hitomi, Takahiro Miyake, Ichiro Umemura, Takatoshi Kosaka, Genji IwasakiAbstract:On the basis of the Pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
