70298-89-4Relevant articles and documents
Synthesis and biological assessment of 4,1-benzothiazepines with neuroprotective activity on the Ca2+ overload for the treatment of neurodegenerative diseases and stroke
Arribas, Raquel L.,Braun-Cornejo, María,De Los Ríos, Cristóbal,Estrada-Valencia, Martín,Moreno-Castro, Manuel,Pérez-Marín, Raquel,Rubio-Alarcón, Marcos,Viejo, Lucía
, (2021/08/09)
In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.
Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase
Madak, Joseph T.,Cuthbertson, Christine R.,Miyata, Yoshinari,Tamura, Shuzo,Petrunak, Elyse M.,Stuckey, Jeanne A.,Han, Yanyan,He, Miao,Sun, Duxin,Showalter, Hollis D.,Neamati, Nouri
, p. 5162 - 5186 (2018/05/15)
We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability (F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.
Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors
Bonafoux, Dominique,Nanthakumar, Suganthini,Bandarage, Upul K.,Memmott, Christine,Lowe, Derek,Aronov, Alex M.,Bhisetti, Govinda Rao,Bonanno, Kenneth C.,Coll, Joyce,Leeman, Joshua,Lepre, Christopher A.,Lu, Fan,Perola, Emanuele,Rijnbrand, Rene,Taylor, William P.,Wilson, Dean,Zhou, Yi,Zwahlen, Jacque,Ter Haar, Ernst
, p. 7138 - 7151 (2016/08/24)
There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 μM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.