- Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes
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A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α1-adrenergic receptor (α1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α1A-, α1B-, and α1D-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6- dione (34) showed the best affinity for the α1A-AR (pKi= 8.74) and 10-fold selectivity compared to the other two α1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α1-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α1D-AR ligands.
- Romeo, Giuseppe,Materia, Luisa,Modica, Maria N.,Pittalà, Valeria,Salerno, Loredana,Siracusa, Maria A.,Manetti, Fabrizio,Botta, Maurizio,Minneman, Kenneth P.
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experimental part
p. 2676 - 2690
(2011/07/08)
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- Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors
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During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead ary
- Wilson, Kenneth J.,Illig, Carl R.,Chen, Jinsheng,Wall, Mark J.,Ballentine, Shelley K.,Desjarlais, Renee L.,Chen, Yanmin,Schubert, Carsten,Donatelli, Robert,Petrounia, Ioanna,Crysler, Carl S.,Molloy, Christopher J.,Chaikin, Margery A.,Manthey, Carl L.,Player, Mark R.,Tomczuk, Bruce E.,Meegalla, Sanath K.
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scheme or table
p. 3925 - 3929
(2010/09/03)
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- INHIBITORS OF C-FMS KINASE
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The invention is directed to compounds of Formula I: wherein Z, X, J, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, es
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Page/Page column 24
(2008/06/13)
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