Tanaka, Yuta published the artcileDiscovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore, Formula: C6H4ClNO2, the publication is Journal of Medicinal Chemistry (2022), 65(5), 4270-4290, database is CAplus and MEDLINE.
Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher’s disease and has been suggested as a potential target for treating Parkinson’s disease. Herein, authors report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with I. The ring opening of I resulted in another potent GCS inhibitor with a lower toxicol. risk, II, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, authors discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.
Journal of Medicinal Chemistry published new progress about 6313-54-8. 6313-54-8 belongs to chlorides-buliding-blocks, auxiliary class Pyridine,Chloride,Carboxylic acid, name is 2-Chloroisonicotinic acid, and the molecular formula is C19H14Cl2, Formula: C6H4ClNO2.
Referemce:
https://en.wikipedia.org/wiki/Chloride,
Chlorides – an overview | ScienceDirect Topics