122243-30-5Relevant academic research and scientific papers
COMPOUNDS AND USES THEREOF
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Page/Page column 204-205, (2021/08/06)
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
PREPARATION PROCESS OF PERFLUOROALKYL COMPOUND WITH MONOHYDROPERFLUOROALKANE AS STARTING MATERIAL
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Paragraph 0072-0076; 0134-0135, (2019/06/17)
A simple production process is provided of a perfluoroalkyl compound that uses monohydroperfluoroalkane as a starting material, the perfluoroalkyl compound being an important intermediate of organic electronic materials, medicine, agricultural chemicals,
Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ? S-X) Interaction for Conformational Constraint
Pennington, Lewis D.,Bartberger, Michael D.,Croghan, Michael D.,Andrews, Kristin L.,Ashton, Kate S.,Bourbeau, Matthew P.,Chen, Jie,Chmait, Samer,Cupples, Rod,Fotsch, Christopher,Helmering, Joan,Hong, Fang-Tsao,Hungate, Randall W.,Jordan, Steven R.,Kong, Ke,Liu, Longbin,Michelsen, Klaus,Moyer, Carolyn,Nishimura, Nobuko,Norman, Mark H.,Reichelt, Andreas,Siegmund, Aaron C.,Sivits, Glenn,Tadesse, Seifu,Tegley, Christopher M.,Van, Gwyneth,Yang, Kevin C.,Yao, Guomin,Zhang, Jiandong,Lloyd, David J.,Hale, Clarence,St. Jean, David J.
supporting information, p. 9663 - 9679 (2016/01/12)
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ?S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.
Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016
Wan, Zhao-Kui,Chenail, Eva,Li, Huan-Qiu,Kendall, Christopher,Wang, Youchu,Gingras, Stephane,Xiang, Jason,Massefski, Walter W.,Mansour, Tarek S.,Saiah, Eddine
scheme or table, p. 7048 - 7055 (2011/10/30)
Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.
