59851-50-2Relevant academic research and scientific papers
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.
A New Synthesis of Cyclic Ureas, Cyclic Urethanes, and a Quinazolinedione. Selenium-Assisted Carbonylation of Aromatic Amines with Carbon Monoxide
Yoshida, Tohru,Kambe, Nobuaki,Murai, Shinji,Sonoda, Noboru
, p. 1793 - 1800 (2007/10/02)
Five-, six-, and seven-membered cyclic ureas were synthesized in excellent yields from various aromatic diamines by reaction with carbon monoxide and a stoichiometric or excess amount of selenium in the presence of an oxidizing agent such as oxygen or dimethyl sulfoxide producing selectively the five- and six-membered cyclic ureas.In the case of 2-(2-aminoethyl)aniline under the catalytic conditions, intra- and intermolecular carbonylation competed resulting in the formation of a mixture of the seven-membered cyclic urea, 1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one and the acyclic urea, 1,3-bisurea.The distribution ratio of these two products varied depending on the reaction conditions, but selective formation of the cyclic urea was attained only when a stoichiometric or excess amount of selenium was used.In addition to the above diamino compounds, 2-carbamoylaniline, 2-amino-3-pyridinol, and 2-(hydroxymethyl)-aniline also underwent similar carbonylation to give 2,4(1H,3H)-quinazolinedione, oxazolopyridin-2-(3H)-one, and 1,4-dihydro-2H-3,1-benzoxazin-2-one, respectively.
