52311-20-3Relevant articles and documents
Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases
He, Xiaohui,Da Ros, Sara,Nelson, John,Zhu, Xuefeng,Jiang, Tao,Okram, Barun,Jiang, Songchun,Michellys, Pierre-Yves,Iskandar, Maya,Espinola, Sheryll,Jia, Yong,Bursulaya, Badry,Kreusch, Andreas,Gao, Mu-Yun,Spraggon, Glen,Baaten, Janine,Clemmer, Leah,Meeusen, Shelly,Huang, David,Hill, Robert,Nguyen-Tran, Van,Fathman, John,Liu, Bo,Tuntland, Tove,Gordon, Perry,Hollenbeck, Thomas,Ng, Kenneth,Shi, Jian,Bordone, Laura,Liu, Hong
supporting information, p. 1048 - 1053 (2017/10/18)
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathological roles of NOD2 pathway. To search for selective RIPK2 inhibitors, we employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models.
Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite
Beaulieu, Pierre L.,Bolger, Gordon,Duplessis, Martin,Gagnon, Alexandre,Garneau, Michel,Stammers, Timothy,Kukolj, George,Duan, Jianmin
, p. 1135 - 1139 (2015/02/19)
A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
