81215-40-9Relevant articles and documents
Discovery of 4-benzoylpiperidine and 3-(piperidin-4-yl)benzo[d]isoxazole derivatives as potential and selective GlyT1 inhibitors
Liu, Yang,Guo, Lin,Duan, Hongliang,Zhang, Liming,Jiang, Neng,Zhen, Xuechu,Shen, Jianhua
, p. 40964 - 40977 (2015/05/20)
Regulation of glycine transporter 1 (GlyT1) activity is a currently investigated strategy in drug discovery for schizophrenia. This study developed a series of new 4-benzoylpiperidine derivatives as GlyT1 inhibitors by bioisosteric replacement and mimicking of the pyridine ring of RG1678. Among the 4-benzoylpiperidine derivatives, 23q showed an IC50 of 30 nM. Preliminary optimization of the blood-brain barrier penetration led to the discovery of 3-(piperidin-4-yl)benzo[d]isoxazole derivatives. Both series showed good selectivity over GlyT2, D1, D2, D3, 5-HT1A and 5-HT2A receptors. Moreover, behavioral testing showed 23q (40 mg kg-1, intragastric) can inhibit the hyperlocomotion induced by acute treatment of phencyclidine, and improve the impaired negative and cognitive symptoms in chronic phencyclidine-induced C57BL/6J mice. An interesting finding showed that 3-(piperidin-4-yl)benzo[d]isoxazole was a privileged scaffold of atypical antipsychotic agents but exhibited high selectivity and potency as a GlyT1 inhibitor.
Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors
Chenna, Bala Chandra,King, Jason R.,Shinkre, Bidhan A.,Glover, Amanda L.,Lucius, Aaron L.,Velu, Sadanandan E.
experimental part, p. 3752 - 3761 (2010/11/17)
Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead in
Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in A Regioselective Aniline Synthesis
Davies, Ian W.,Marcoux, Jean-Francois,Kuethe, Jeffery T.,Lankshear, Michael D.,Taylor, Jeremy D. O.,Tsou, Nancy,Dormer, Peter G.,Hughes, David L.,Houk,Guner, Vildan
, p. 1298 - 1308 (2007/10/03)
Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (kH/D 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.
