1254360-78-5Relevant articles and documents
Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants
Nageswara Rao, Desaboini,Zephyr, Jacqueto,Henes, Mina,Chan, Elise T.,Matthew, Ashley N.,Hedger, Adam K.,Conway, Hasahn L.,Saeed, Mohsan,Newton, Alicia,Petropoulos, Christos J.,Huang, Wei,Kurt Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
supporting information, p. 11972 - 11989 (2021/09/06)
The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use - grazoprevir, glecaprevir, and voxilaprevir - are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 m
Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors
Zak, Mark,Yuen, Po-Wai,Liu, Xiongcai,Patel, Snahel,Sampath, Deepak,Oeh, Jason,Liederer, Bianca M.,Wang, Weiru,O'Brien, Thomas,Xiao, Yang,Skelton, Nicholas,Hua, Rongbao,Sodhi, Jasleen,Wang, Yunli,Zhang, Lei,Zhao, Guiling,Zheng, Xiaozhang,Ho, Yen-Ching,Bair, Kenneth W.,Dragovich, Peter S.
, p. 8345 - 8368 (2016/10/03)
NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
