174799-52-1Relevant articles and documents
Exploitation of the Ugi-Joullié Reaction in the Synthesis of Libraries of Drug-Like Bicyclic Hydantoins
Firth, James D.,Zhang, Rong,Morgentin, Rémy,Guilleux, Rachel,Kalliokoski, Tuomo,Warriner, Stuart,Foster, Richard,Marsden, Stephen P.,Nelson, Adam
, p. 2391 - 2406 (2015)
A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi-Joullié reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.
Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis
Chianelli, Donatella,Rucker, Paul V.,Roland, Jason,Tully, David C.,Nelson, John,Liu, Xiaodong,Bursulaya, Badry,Hernandez, Eloy D.,Wu, Jane,Prashad, Mahavir,Schlama, Thierry,Liu, Yugang,Chu, Alan,Schmeits, James,Huang, David J.,Hill, Robert,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Groessl, Todd,McNamara, Peter,Liu, Bo,Richmond, Wendy,Sancho-Martinez, Ignacio,Phimister, Andrew,Seidel, H. Martin,Badman, Michael K.,Joseph, Sean B.,Laffitte, Bryan,Molteni, Valentina
supporting information, p. 3868 - 3880 (2020/05/27)
Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.
Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase
Zhang, Rong,McIntyre, Patrick J.,Collins, Patrick M.,Foley, Daniel J.,Arter, Christopher,von Delft, Frank,Bayliss, Richard,Warriner, Stuart,Nelson, Adam
supporting information, p. 6831 - 6839 (2019/05/10)
Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3-rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.
