- Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014
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A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC50 lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
- Brodney, Michael A.,Auperin, David D.,Becker, Stacey L.,Bronk, Brian S.,Brown, Tracy M.,Coffman, Karen J.,Finley, James E.,Hicks, Carol D.,Karmilowicz, Michael J.,Lanz, Thomas A.,Liston, Dane,Liu, Xingrong,Martin, Barbara-Anne,Nelson, Robert B.,Nolan, Charles E.,Oborski, Christine E.,Parker, Christine P.,Richter, Karl E.G.,Pozdnyakov, Nikolay,Sahagan, Barbara G.,Schachter, Joel B.,Sokolowski, Sharon A.,Tate, Barbara,Wood, Douglas E.,Wood, Kathleen M.,Van Deusen, Jeffrey W.,Zhang, Lei
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scheme or table
p. 2637 - 2640
(2011/06/20)
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- A concise method for the synthesis of 2-tetralone by titanium tetrachloride-promoted cyclization of 4-aryl-2-hydroxybutanal diethyl acetal
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4-Aryl-2-hydroxybutanal diethyl acetal, prepared from the reaction of benzyl Grignard reagent and glycidaldehyde diethyl acetal, was treated with titanium tetrachloride to give 2-tetralone in good yield. This highly efficient transformation involves tande
- Hon, Yung-Son,Devulapally, Rammohan
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scheme or table
p. 5713 - 5715
(2009/12/09)
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- The synthesis of novel cis-α-substituted-β-aminotetralins
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Teteralones were converted, in 1 to 3 steps, to α-substituted tetralones. Subsequent reductive amination with ammonium acetate/sodium cyanoborohydride gave the corresponding α-substituted-β-aminotetralins, on a multigram scale, with minimal chromatography for the entire transformation.
- Youngman, Mark A.,Willard, Nicole M.,Dax, Scott L.,McNally, James J.
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p. 2215 - 2227
(2007/10/03)
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- Antihyperglycemic Activity of Novel Naphthalenyl 3H-1,2,3,5-Oxathiadiazole 2-Oxides
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A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus.Substitution at the 1-,5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4--3H-1,2,3,5-oxathiadiazole 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.
- Ellingboe, John W.,Lombardo, Louis J.,Alessi, Thomas R.,Nguyen, Thomas T.,Guzzo, Frieda,et al.
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p. 2485 - 2493
(2007/10/02)
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- 5-, 6-, 7- and 8-amino-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydrophthalenes: Centrally acting DA and 5-HT(1A) agonists
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5-, 6-, 7- and 8-Amino-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene were synthesized and compared with the corresponding phenolic compounds in vivo and in vitro for their effects on central serotonergic (5-HT(1A)) and dopaminergic (D2) systems. The 5- and 8-amino isomers surprisingly showed a 100-fold lower affinity for D2 and 5-HT(1A) receptors, respectively, than their corresponding phenols. This was also reflected in vivo. The 6-amino- and hydroxy-isomers were equipotent, while the 7-amino compound showed in vivo effects both on dopaminergic and serotonergic systems, the latter not being noticed in vitro. Intermediates 8-bromo-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene and 2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene-8-carboxylic acid methyl ester were also tested and found to be quite potent 5-HT(1A) agonists.
- Stjernlof,Elebring,Andersson,Svensson,Svensson,Ekman,Carlsson,Wikstrom
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p. 693 - 701
(2007/10/02)
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- (S)- and (R)-8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1- carbaldehyde: A new class of orally active 5-HT(1A)-receptor agonists
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The enantiomers of 6,7,8,9-tetrahydro-N,N-di-n-propyl-3H-benz[e]indol-8- amine (S-(-)-2b and R-(+)-2b) and their corresponding 1-formyl analogs (S-(- )-6 and R-(+)-6 were prepared and evaluated pharmacologically for serotonergic and dopaminergic activity. The introduction of a formyl group in the 1-position shifted the pharmacological profile of 2b from a mixed D2/5- HT(1A) agonists to a selective 5-HT(1A) agonist (6). The enantiomers of 6 were agonists with full intrinsic activity and had an affinity comparable to that of 8-hydroxy-2-(di-n-propylamino)tetrahydronaphthalene (8-OH-DPAT). In contrast to 8-OH-DPAT, the enantiomers of compound 6 were found to have good oral availability.
- Stjernlof,Gullme,Elebring,Andersson,Wikstrom,Lagerquist,Svensson,Ekman,Carlsson,Sundell
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p. 2059 - 2065
(2007/10/02)
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