- Design and Optimization of an Acyclic Amine Series of TRPV4 Antagonists by Electronic Modulation of Hydrogen Bond Interactions
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Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopp
- Patterson, Jaclyn R.,Terrell, Lamont R.,Donatelli, Carla A.,Holt, Dennis A.,Jolivette, Larry J.,Rivero, Ralph A.,Roethke, Theresa J.,Shu, Arthur,Stoy, Patrick,Ye, Guosen,Youngman, Mark,Lawhorn, Brian G.
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- NEW BICYCLIC DERIVATIVES HAVING BETA2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES
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The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
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- COMPOUNDS FOR THE REDUCTION OF BETA-AMYLOID PRODUCTION
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Compounds of the formula (I) are provided, including pharmaceutically acceptable salts thereof: which modulate β-amyloid peptide (β-AP) production, and are useful in the treatment of Alzheimer's Disease and other conditions affected by -amyloid peptide (β-AP) production.
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- Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the α6* subtype
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Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6 subunit-containing neuronal nicotinic rece
- Breining, Scott R.,Bencherif, Merouane,Grady, Sharon R.,Whiteaker, Paul,Marks, Michael J.,Wageman, Charles R.,Lester, Henry A.,Yohannes, Daniel
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scheme or table
p. 4359 - 4363
(2010/04/05)
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- Regio- and enantioselective control in the reactions of α-(N-Carbamoyl)alkylcuprates with allylic phosphates
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α-(N-Carbamoyl)alkylcuprates (RCuCNLi or R2CuLi) react with allylic phosphates to afford homoallylic amines in good chemical yields. Regioselectivity is governed by steric factors in both the cuprate reagent and phosphate substrate and systems can be designed to give either the S N2′ or SN2 substitution product cleanly. Excellent enantioselectivities can be achieved with either a scalemic α-di[(N- carbamoyl)-alkyl]cuprate and an achiral phosphate or with a scalemic allylic phosphate and an achiral cuprate reagent.
- Dieter, R. Karl,Gore, Vinayak K.,Chen, Ningyi
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p. 763 - 766
(2007/10/03)
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- Pharmaceutical compositions and methods for use
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Pharmaceutical compositions incorporate aryl substituted olefinic amine compounds. Representative compounds are (3E)-N-methyl-4-[3-(5-nitro-6-aminopyridin)yl]-3-buten-1-amine, (3E)-N-methyl-4-[3-(5-(N-benzylcarboxamido)pyridin)yl]-3-buten-1-amine, (4E)-N-methyl-5-[5-(2-aminopyrimidin)yl]-4-penten-2-amine, (4E)-N-methyl-5-(3-(5-aminopyridin)yl)-4-penten-2-amine, (3E)-N-methyl-4-(3-(5-isobutoxypyridin)yl)-3-buten-1-amine, (3E)-N-methyl-4-(3-(1-oxopyridin)yl)-3-buten-1-amine, (3E)-N-methyl-4-(3-(5-ethylthiopyridin)yl)-3-buten-1-amine, (4E)-N-methyl-5-(3-(5-trifluoromethylpyridin)yl)-4-penten-2-amine and (4E)-N-methyl-5-(3-(5-hydroxypyridin)yl)-4-penten-2-amine.
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- TC-2559: A novel orally active ligand selective at neuronal acetylcholine receptors
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TC-2559 [(E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine] is a novel nicotinic agonist markedly more selective than recently reported novel nicotinic receptor ligands (selectivity ratio for central nervous system (CNS) to peripheral nervous system (PNS) > 4000). TC-2559 competes effectively with [3H]-nicotine binding (K(i) = 5 nM) but not with [125I]-bungarotoxin (> 50,000 nM). Dopamine release from striatal synaptosomes and ion flux from thalamic synaptosomes indicate that TC-2559 is potent and efficacious in the activation of CNS receptors and significantly reduced glutamate-induced neurotoxicity in vitro. TC-2559 has no detectable effects on muscle and ganglion-type nicotinic acetylcholine receptors at concentrations up to 1 mM. TC-2559 significantly attenuates scopolamine-induced cognitive deficits in a step-through passive avoidance task. Acute and repeated oral dosing of TC-2559 enhances performance in a radial arm maze task. In contrast to the effects of equimolar concentrations of (-) nicotine, TC-2559 does not induce hypothermia and locomotor activity is not enhanced following repeated daily administration of 14 days. TC-2559 has a markedly enhanced CNS-PNS selectivity ratio and an intra-CNS selectivity as evidenced by the improved cognition without increased locomotor activity. The in vitro and in vivo studies in the present study suggest that TC-2559 has the desired profile to be further evaluated as a potential therapeutic agent for neurodegenerative diseases. (C) 2000 Elsevier Science B.V.
- Bencherif, Merouane,Bane, Andrew J,Miller, Craig H,Dull, Gary M,Gatto, Gregory J
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