79099-00-6Relevant articles and documents
Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening
Wellaway, Christopher R.,Amans, Dominique,Bamborough, Paul,Barnett, Heather,Bit, Rino A.,Brown, Jack A.,Carlson, Neil R.,Chung, Chun-Wa,Cooper, Anthony W. J.,Craggs, Peter D.,Davis, Robert P.,Dean, Tony W.,Evans, John P.,Gordon, Laurie,Harada, Isobel L.,Hirst, David J.,Humphreys, Philip G.,Jones, Katherine L.,Lewis, Antonia J.,Lindon, Matthew J.,Lugo, Dave,Mahmood, Mahnoor,McCleary, Scott,Medeiros, Patricia,Mitchell, Darren J.,O'Sullivan, Michael,Le Gall, Armelle,Patel, Vipulkumar K.,Patten, Chris,Poole, Darren L.,Shah, Rishi R.,Smith, Jane E.,Stafford, Kayleigh A. J.,Thomas, Pamela J.,Vimal, Mythily,Wall, Ian D.,Watson, Robert J.,Wellaway, Natalie,Yao, Gang,Prinjha, Rab K.
, p. 714 - 746 (2020)
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
Chemical modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2h-benzo[d]imidazole-2-one scaffold as a novel NLRP3 inhibitor
Bertinaria, Massimo,Blua, Federica,Boscaro, Valentina,Gallicchio, Margherita,Gastaldi, Simone,Gianquinto, Eleonora,Giorgis, Marta,Macdonald, Justin A.,Marini, Elisabetta,Sandall, Christina F.,Spyrakis, Francesca
, (2021/07/13)
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein– ligand binding that might explain the activity of the compounds.
Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias
Kennedy, Nicole M.,Schmid, Cullen L.,Ross, Nicolette C.,Lovell, Kimberly M.,Yue, Zhizhou,Chen, Yen Ting,Cameron, Michael D.,Bohn, Laura M.,Bannister, Thomas D.
, p. 8895 - 8907 (2018/10/05)
While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal βarrestin-mediated signaling because MOR agonist-treated βarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/βarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.
