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Brian R. Bond - One of the best experts on this subject based on the ideXlab platform.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as Potent Phosphodiesterase 5 (PDE5) Inhibitors.
ChemInform, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:A series of 32 title compounds are prepared and tested as phosphodiesterase 5 (PDE5) Inhibitors.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) Inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 Inhibitors resulting in the advancement of a clinical candidate.
Robert Hughes - One of the best experts on this subject based on the ideXlab platform.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as Potent Phosphodiesterase 5 (PDE5) Inhibitors.
ChemInform, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:A series of 32 title compounds are prepared and tested as phosphodiesterase 5 (PDE5) Inhibitors.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) Inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 Inhibitors resulting in the advancement of a clinical candidate.
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optimization of the aminopyridopyrazinones class of PDE5 Inhibitors discovery of 3 trans 4 hydroxycyclohexyl amino 7 6 methoxypyridin 3 yl 1 2 propoxyethyl pyrido 3 4 b pyrazin 2 1h one
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Robert Hughes, John K. Walker, Jerry W. Cubbage, Yvette M. Fobian, Steve E. Heasley, Alan G. Benson, Jon E Jacobsen, Joseph D Rogier, Radhika M Blevisbal, Dafydd R. OwenAbstract:We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 Inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
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identification synthesis and sar of amino substituted pyrido 3 2b pyrazinones as potent and selective PDE5 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Dafydd R. Owen, Robert Hughes, John K. Walker, Jon E Jacobsen, John N Freskos, David Louis Brown, Andrew Simon Bell, Christopher Phillips, Brent V MischkeAbstract:A new class of potent and selective PDE5 Inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure–activity relationships are also presented.
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Investigation of aminopyridiopyrazinones as PDE5 Inhibitors: Evaluation of modifications to the central ring system.
2009Co-Authors: Robert Hughes, John K. Walker, Jerry W. Cubbage, Yvette M. Fobian, D. Joseph Rogier, Steve E. Heasley, Radhika M. Blevis-bal, Alan G. Benson, Dafydd R. Owen, E. Jon JacobsenAbstract:Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 Inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
John K. Walker - One of the best experts on this subject based on the ideXlab platform.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as Potent Phosphodiesterase 5 (PDE5) Inhibitors.
ChemInform, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:A series of 32 title compounds are prepared and tested as phosphodiesterase 5 (PDE5) Inhibitors.
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1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Michael B. Tollefson, Brad A. Acker, Eric Jon Jacobsen, Robert Hughes, John K. Walker, David Nathan Abraham Fox, Michael John Palmer, Sandra K. Freeman, Brian R. BondAbstract:1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) Inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 Inhibitors resulting in the advancement of a clinical candidate.
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optimization of the aminopyridopyrazinones class of PDE5 Inhibitors discovery of 3 trans 4 hydroxycyclohexyl amino 7 6 methoxypyridin 3 yl 1 2 propoxyethyl pyrido 3 4 b pyrazin 2 1h one
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Robert Hughes, John K. Walker, Jerry W. Cubbage, Yvette M. Fobian, Steve E. Heasley, Alan G. Benson, Jon E Jacobsen, Joseph D Rogier, Radhika M Blevisbal, Dafydd R. OwenAbstract:We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 Inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
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identification synthesis and sar of amino substituted pyrido 3 2b pyrazinones as potent and selective PDE5 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Dafydd R. Owen, Robert Hughes, John K. Walker, Jon E Jacobsen, John N Freskos, David Louis Brown, Andrew Simon Bell, Christopher Phillips, Brent V MischkeAbstract:A new class of potent and selective PDE5 Inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure–activity relationships are also presented.
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Investigation of aminopyridiopyrazinones as PDE5 Inhibitors: Evaluation of modifications to the central ring system.
2009Co-Authors: Robert Hughes, John K. Walker, Jerry W. Cubbage, Yvette M. Fobian, D. Joseph Rogier, Steve E. Heasley, Radhika M. Blevis-bal, Alan G. Benson, Dafydd R. Owen, E. Jon JacobsenAbstract:Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 Inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
Linda Xiao - One of the best experts on this subject based on the ideXlab platform.
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determination of phosphodiesterase 5 PDE5 Inhibitors in instant coffee premixes using liquid chromatography high resolution mass spectrometry lc hrms
Talanta, 2019Co-Authors: Ahmad Yusri Mohd Yusop, Linda XiaoAbstract:Abstract As a widely consumed beverage, coffee tends to be a target for intentional adulteration. This study describes the application of modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) coupled to liquid chromatography-high-resolution mass spectrometry (LC-HRMS) for simultaneous screening, identification, and quantification of undeclared phosphodiesterase 5 (PDE5) Inhibitors in instant coffee premixes (ICPs). The mass spectrometer was operated in auto MS/MS acquisition for simultaneous MS and MS/MS experiments. Qualitative establishments from the suspected-target screening and targeted identification processes led to an unambiguous analyte assignment from the protonated molecule ([M+H]+) precursor ion which is subsequently used for quantification of 23 targeted PDE5 Inhibitors. The analytical method validation covered specificity, linearity, range, accuracy, limit of detection (LOD), limit of quantification (LOQ), precisions, matrix effect (ME), and extraction recovery (RE). The specificity was established using the optimised chromatographic separation as well as the distinguishable [M+H]+ precursor ion. The linearity of each target analyte was demonstrated with a coefficient of determination (r2) of >0.9960 over the expected range of sample concentrations. The accuracy ranged from 88.1%–119.3% with LOD and LOQ of
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Data on the optimisation and validation of a liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to establish the presence of phosphodiesterase 5 (PDE5) Inhibitors in instant coffee premixes.
Data in brief, 2019Co-Authors: Ahmad Yusri Mohd Yusop, Linda XiaoAbstract:Abstract This paper presents the data on the optimisation and validation of a liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to establish the presence of phosphodiesterase 5 (PDE5) Inhibitors and their analogues as adulterants in instant coffee premixes. The method development data covered chromatographic optimisation for better analyte separation and isomeric resolution, mass spectrometry optimisation for high sensitivity and sample preparation optimisation for high extraction recovery (RE) and low matrix effect (ME). The validation data covered specificity, linearity, range, accuracy, limit of detection, limit of quantification, precisions, ME, and RE. The optimisation and validation data presented here is related to the article: “Determination of phosphodiesterase 5 (PDE5) Inhibitors in instant coffee premixes using liquid chromatography-high-resolution mass spectrometry (LC-HRMS)” Mohd Yusop et al., 2019.
Hai-bin Luo - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket.
Journal of Medicinal Chemistry, 2020Co-Authors: Zhang Tianhua, Zengwei Lai, Suying Yuan, Yi-you Huang, Guoqiang Dong, Chunquan Sheng, Hai-bin LuoAbstract:Clinical use of phosphodiesterase-5 (PDE5) Inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 Inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 A movement of their Cα atoms. This movement directly blocks the binding of substrate/Inhibitors to the PDE5 active site, which is different from all traditional PDE5 Inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
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optimization of chromeno 2 3 c pyrrol 9 2 h ones as highly potent selective and orally bioavailable PDE5 Inhibitors structure activity relationship x ray crystal structure and pharmacodynamic effect on pulmonary arterial hypertension
Journal of Medicinal Chemistry, 2018Co-Authors: Yadan Huang, Yi-you Huang, Yiping Chen, Haiju Geng, Tianhua Zhang, Chen Zhang, Lei Guo, Jianwen Chen, Hai-bin LuoAbstract:To further explore the structure–activity relationship around the chromeno[2,3-c]pyrrol-9(2H)-one scaffold, 19 derivatives as Inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 Inhibitors.
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discovery of 3 4 hydroxybenzyl 1 thiophen 2 yl chromeno 2 3 c pyrrol 9 2h one as a phosphodiesterase 5 inhibitor and its complex crystal structure
Biochemical Pharmacology, 2014Co-Authors: Na Na Shang, Yong Xian Shao, Ying Hong Cai, Matthew Guan, Manna Huang, Wenjun Cui, Lei Huang, Hai-bin LuoAbstract:Phosphodiesterase-5 (PDE5) Inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 Inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 Inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2A resolution and showed that 57 occupies the same pocket as other PDE5 Inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE Inhibitors.