Knutson, Daniel E Kodali, Revathi Divovic, Branka Treven, Marco Stephen, Michael Rajesh Zahn, Nicolas M Dobričić, Vladimir Huber, Alec T Meirelles, Matheus A Verma, Ranjit S
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Published in
Journal of medicinal chemistry
Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal orofacial pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized and their in vitro metabolic stability and cytotox...
Thamban Chandrika, Nishad Shrestha, Sanjib K Ngo, Huy X Tsodikov, Oleg V Howard, Kaitlind C Garneau-Tsodikova, Sylvie
Published in
Journal of medicinal chemistry
The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and ...
Goffin, Eric Drapier, Thomas Larsen, Anja Probst Geubelle, Pierre Ptak, Christopher P Laulumaa, Saara Rovinskaja, Karoline Gilissen, Julie Tullio, Pascal de Olsen, Lars
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Published in
Journal of medicinal chemistry
We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experime...
Witten, Michael R Wissler, Lisa Snow, Melanie Geschwindner, Stefan Read, Jon A Brandon, Nicholas J Nairn, Angus C Lombroso, Paul J Käck, Helena Ellman, Jonathan A
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Published in
Journal of medicinal chemistry
Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the obs...
Bezençon, Olivier Heidmann, Bibia Siegrist, Romain Stamm, Simon Richard, Sylvia Pozzi, Davide Corminboeuf, Olivier Roch, Catherine Kessler, Melanie Ertel, Eric A
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Published in
Journal of medicinal chemistry
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. ...
García-Cárceles, Javier Decara, Juan M Vázquez-Villa, Henar Rodríguez, Ramón Codesido, Eva Cruces, Jacobo Brea, José Loza, María I Alén, Francisco Botta, Joaquin
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Published in
Journal of medicinal chemistry
The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA24...
Churcher, Ian
Published in
Journal of medicinal chemistry
Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this perspective, the brief history of the field is surveyed from a drug discovery ...
Comegna, Daniela Zannetti, Antonella Del Gatto, Annarita de Paola, Ivan Russo, Luigi Di Gaetano, Sonia Liguoro, Annamaria Capasso, Domenica Saviano, Michele Zaccaro, Laura
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Published in
Journal of medicinal chemistry
Herein we report the synthesis and biological characterization of the novel peptide ψRGDechi as the first step towards novel targeted theranostics in melanoma. This pseudo-peptide is designed from our previously reported RGDechi peptide, known to bind selectively αvβ3 integrin, and differs for a modified amide bond at the main protease cleavage sit...
Chen, Jinshui Song, Yun Bojadzic, Damir Tamayo-Garcia, Alejandro Landin, Ana Marie Blomberg, Bonnie B Buchwald, Peter
Published in
Journal of medicinal chemistry
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors ...
Kolář, Michal H Tabarrini, Oriana
Published in
Journal of medicinal chemistry
Halogen bonding (X-bonding) has attracted notable attention among noncovalent interactions. This highly directional attraction between a halogen atom and an electron donor has been exploited in knowledge-based drug design. A great deal of information has been gathered about X-bonds in protein-ligand complexes, as opposed to nucleic acid complexes. ...
