- Inhibitors of the glycine transporter type-2 (GlyT-2): synthesis and biological activity of benzoylpiperidine derivatives.
-
A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpiperidine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n=1) was observed relative to the corresponding 3-carbon homolog (n=2).
- Wolin, Ronald L,Santillan Jr., Alejandro,Tang, Liu,Huang, Charles,Jiang, Xiaoxia,Lovenberg, Timothy W
-
p. 4511 - 4532
(2007/10/03)
-
- Oxo-piperazine derivatives of N-arylpiperazinones as inhibitors of farnesyltransferase
-
The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmac
- Dinsmore, Christopher J,Bergman, Jeffrey M,Wei, Donna D,Zartman,Davide, Joseph P,Greenberg, Ian B,Liu, Dongming,O'Neill, Timothy J,Gibbs, Jackson B,Koblan, Kenneth S,Kohl, Nancy E,Lobell, Robert B,Chen, I-Wu,McLoughlin, Debra A,Olah, Timothy V,Graham, Samuel L,Hartman, George D,Williams, Theresa M
-
p. 537 - 540
(2007/10/03)
-
- Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT(2A) and α1 receptor binding affinity
-
A series of triazolopyridine derivatives (compounds 2a-1) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT(2A) and α1 receptors. All of the synthesized compounds show a decrease of affinity for both 5HT(2A) and α1 receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an α position to the aliphatic nitrogen atom N1. These compounds showed a decrease of affinity only for the α1 receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)- 2c showed the most significant differences between 5HT(2A) and α1 receptor affinity (IC50 values) and among the corresponding functional properties (pA2 values). Since (S)-2c cannot generate the metabolite 4-(3- chlorophenyl)piperazine this product was selected for further pharmacological studies.
- Giannangeli, Marilena,Cazzolla, Nicola,Luparini, Maria Rita,Magnani, Maurizio,Mabilia, Massimo,Picconi, Giuseppe,Tomaselli, Mauro,Baiocchi, Leandro
-
p. 336 - 345
(2007/10/03)
-
- Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding
-
A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold-Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4- yl)methyl]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) in the Bezold-Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.
- Heidempergher, Franco,Pillan, Antonio,Pinciroli, Vittorio,Vaghi, Fabrizio,Arrigoni, Claudio,Bolis, Giorgio,Caccia, Carla,Dho, Luciano,McArthur, Robert,Varasi, Mario
-
p. 3369 - 3380
(2007/10/03)
-
- The Use of 2-Oxazolidinones as Latent Aziridine Equivalents. 2. Aminoethylation of Aromatic Amines, Phenols, and Thiophenols
-
The utility of 2-oxazolidinones 1 as latent, carboxylated aziridine functionalities was examined.Reaction of 2-oxazolidinone (1a), 3-methyl2-oxazolidinone (1b), 3-(phenylmethyl)-2-oxazolidinone (1c), 3-phenyl-2-oxazolidinone (1d) 4,4-dimethyl-2-oxazolidinone (1e), and 5-ethyl-2-oxazolidinone (1f) with aromatic amine salts, phenol, or thiophenols at elevated temperatures (> 130 deg C) afforded aminoethylated adducts.The aminoethylation occurred with concomitant loss of carbon dioxide to furnish variously substituted N-aryl-1,2-ethanediamines 4, 1-(2-phenoxyethyl)-2-imidazolidinone (8), or 2-(arylthio)ethanamines 9 on reactions of 1 with aromatic amine salts, phenol, and thiophenols, respectively.Imidazolidinone 8 is believed to be a secondary reaction product resulting from the condensation of the initially formed 2-phenoxyethanamine with starting oxazolidinone 1a.The aminoethylation reaction did not proceed with aliphatic amine hydrochlorides or alkyl mercaptans.Preliminary mechanistic pathways for these ring openings were also investigated employing a specific, C-5 deuterium-labeled oxazolidinone 1b-d2.Ring-opening experiments of 1b-d2 with N-methylaniline hydrochloride suggest reaction can occur through either a dioxazolinium 5 and/or 5 intermediate.In contrast, reaction of 1b-d2 with thiophenol suggests ring-opening to proceed only via the dioxazolinium pathway.
- Poindexter, Graham S.,Owens, Donald A.,Dolan, Peter L.,Woo, Edmund
-
p. 6257 - 6265
(2007/10/02)
-
- Aminoethylation process
-
2-Oxazolidinone or N-substituted derivatives thereof are reacted with aromatic amine hydrochlorides at elevated temperatures to produce 1,2-ethanediamines.
- -
-
-