634925-24-9Relevant articles and documents
Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors
Di Martino, Simona,Tardia, Piero,Cilibrasi, Vincenzo,Caputo, Samantha,Mazzonna, Marco,Russo, Debora,Penna, Ilaria,Realini, Natalia,Margaroli, Natasha,Migliore, Marco,Pizzirani, Daniela,Ottonello, Giuliana,Bertozzi, Sine Mandrup,Armirotti, Andrea,Nguyen, Duc,Sun, Ying,Bongarzone, Ernesto R.,Lansbury, Peter,Liu, Min,Skerlj, Renato,Scarpelli, Rita
, p. 3634 - 3664 (2020/04/30)
Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C? mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.
Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine-3-carboxamide derivatives
Lv, Kai,Li, Linhu,Wang, Bo,Liu, Mingliang,Wang, Bin,Shen, Weiyi,Guo, Huiyuan,Lu, Yu
, p. 117 - 125 (2017/06/05)
We report herein the design and synthesis of “novel imidazo [1,2-a]pyridine-3-carboxamides (IPAs)” bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl-N-[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041–2.64 μM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31), opening a new direction for further SAR studies.
SILICON COMPOUNDS AND THEIR USE
-
Page/Page column 36-37, (2010/11/08)
A compound of any of formulas (I) to (V) : wherein at least one of Y and Z includes a Si atom, is of utility in therapy.
