The Experts below are selected from a list of 1122 Experts worldwide ranked by ideXlab platform
Fergus Mctaggart - One of the best experts on this subject based on the ideXlab platform.
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Quinuclidine inhibitors of 2 3 oxidosqualene cyclase lanosterol synthase optimization from lipid profiles
Journal of Medicinal Chemistry, 1999Co-Authors: George Robert Brown, Alan J. Foubister, M. C. Johnson, D M Hollinshead, Elaine Sophie Elizabeth Stokes, David S Clarke, M A Eakin, Steven C Glossop, D Griffiths, Fergus MctaggartAbstract:Novel 3-substituted Quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure−activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted Quinuclidine pharmacophore 18a−c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 ± 11 nM for human and an IC50 value of 124 ± 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 ± 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted Quinuclidines, which were derived from a quinu...
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Quinuclidine inhibitors of 2 3 oxidosqualene cyclase lanosterol synthase optimization from lipid profiles
Journal of Medicinal Chemistry, 1999Co-Authors: Brown George Robert, Alan J. Foubister, M. C. Johnson, D M Hollinshead, David S Clarke, M A Eakin, Steven C Glossop, D Griffiths, Stokes Elaine Sophie Elizabeth, Fergus MctaggartAbstract:Novel 3-substituted Quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted Quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted Quinuclidines, which were derived from a Quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.
Xiaofeng Tong - One of the best experts on this subject based on the ideXlab platform.
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amine catalyzed asymmetric 3 3 annulations of β acetoxy allenoates enantioselective synthesis of 4h pyrans
Journal of the American Chemical Society, 2016Co-Authors: Chunjie Ni, Xiaofeng TongAbstract:The asymmetric (3 + 3) annulations of β′-acetoxy allenoates with either 3-oxo-nitriles or pyrazolones have been realized by using 6′-deoxy-6′-[(l)-N,N-(2,2′-oxidiethyl)-valine amido]quinine (6h) as the catalyst. The three functions of catalyst 6h, including Lewis base (Quinuclidine N), H-bond donor (amide NH), and Bronsted base (morpholine N), cooperatively take crucial roles on the chemo- and enantioselectivity, allowing for the construction of 4H-pyran and 4H-pyrano[2,3-c]pyrazole in high yields and enantioselectivity.
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Amine-Catalyzed Asymmetric (3 + 3) Annulations of β′-Acetoxy Allenoates: Enantioselective Synthesis of 4H‑Pyrans
2016Co-Authors: Xiaofeng TongAbstract:The asymmetric (3 + 3) annulations of β′-acetoxy allenoates with either 3-oxo-nitriles or pyrazolones have been realized by using 6′-deoxy-6′-[(l)-N,N-(2,2′-oxidiethyl)-valine amido]quinine (6h) as the catalyst. The three functions of catalyst 6h, including Lewis base (Quinuclidine N), H-bond donor (amide NH), and Brønsted base (morpholine N), cooperatively take crucial roles on the chemo- and enantioselectivity, allowing for the construction of 4H-pyran and 4H-pyrano[2,3-c]pyrazole in high yields and enantioselectivity
Jinpei Cheng - One of the best experts on this subject based on the ideXlab platform.
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ionic liquid immobilized Quinuclidine catalyzed morita baylis hillman reactions
Journal of Organic Chemistry, 2005Co-Authors: Sanzhong Luo, Jinpei Cheng, Sanzhong LuoAbstract:The ionic liquid-bound Quinuclidine catalyzed Baylis−Hillman reactions were investigated. The IL-supported catalyst showed equally good catalytic activity as compared with its nonimmobilized counterpart. The corresponding Baylis−Hillman adducts were obtained in moderate to high yields in all the cases tested. The IL-supported Quinuclidine can be readily recovered and reused six times without significant loss of catalytic activity.
David C Kombo - One of the best experts on this subject based on the ideXlab platform.
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qm polarized ligand docking accurately predicts the trend in binding affinity of a series of arylmethylene Quinuclidine like derivatives at the α4β2 and α3β4 nicotinic acetylcholine receptors nachrs
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: David C Kombo, Vladimir P Grinevich, Terry Hauser, Serguei S Sidach, Merouane BencherifAbstract:Abstract Compounds containing a Quinuclidine scaffold are promising drug candidates for pharmacological management of the central nervous system (CNS) pathologies implicating nAChRs. We have carried out binding affinity and in-silico docking studies of arylmethylene Quinuclidine-like derivatives at the α4β2 receptor using in-vitro receptor binding assay and comparative modeling, respectively. We found that introducing a hydrogen-bond acceptor into the 3-benzylidene Quinuclidine derivative resulted in a 266-fold increase in binding affinity and confers agonism properties. By contrast, addition of a phenyl group to 3-benzylidene Quinuclidine derivative only results in an 18-fold increase in binding affinity, without conferring agonism. We also found that docking into the orthosteric binding site of the α4β2 nAChR is consistent with the fact that the basic nitrogen atom donates a hydrogen-bond to the carbonyl group of the highly conserved Trp-149, as initially observed by Dougherty and co-workers.1 The experimentally-observed trend in binding affinity at both α4β2 and α3β4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3β4 subtype primarily results from a dampening of both coulombic and cation–π interactions.
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pharmacological properties and predicted binding mode of arylmethylene Quinuclidine like derivatives at the α3β4 nicotinic acetylcholine receptor nachr
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: David C Kombo, Vladimir P Grinevich, Terry Hauser, Serguei S Sidach, Matt S Melvin, Jonpaul Strachan, Joseph Chewning, Nikolai Fedorov, Kartik Tallapragada, Scott R BreiningAbstract:Abstract We have carried out a pharmacological evaluation of arylmethylene Quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1 , 2 and 3 ), displaying submicromolar IC 50 values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3 ), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6 ). Introducing a hydrogen-bond acceptor into the 3-benzylidene Quinuclidine derivative (compound 7 ) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.
Steven C Glossop - One of the best experts on this subject based on the ideXlab platform.
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Quinuclidine inhibitors of 2 3 oxidosqualene cyclase lanosterol synthase optimization from lipid profiles
Journal of Medicinal Chemistry, 1999Co-Authors: George Robert Brown, Alan J. Foubister, M. C. Johnson, D M Hollinshead, Elaine Sophie Elizabeth Stokes, David S Clarke, M A Eakin, Steven C Glossop, D Griffiths, Fergus MctaggartAbstract:Novel 3-substituted Quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure−activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted Quinuclidine pharmacophore 18a−c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 ± 11 nM for human and an IC50 value of 124 ± 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 ± 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted Quinuclidines, which were derived from a quinu...
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Quinuclidine inhibitors of 2 3 oxidosqualene cyclase lanosterol synthase optimization from lipid profiles
Journal of Medicinal Chemistry, 1999Co-Authors: Brown George Robert, Alan J. Foubister, M. C. Johnson, D M Hollinshead, David S Clarke, M A Eakin, Steven C Glossop, D Griffiths, Stokes Elaine Sophie Elizabeth, Fergus MctaggartAbstract:Novel 3-substituted Quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted Quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted Quinuclidines, which were derived from a Quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.
