- Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening
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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.
- 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.
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Read Online
- HETEROCYCLIC COMPOUND, APPLICATION THEREOF, AND COMPOSITION CONTAINING SAME
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A heterocyclic compound represented by formula XI, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, use thereof, and a composition containing the same. The compound is novel in structure and has good STAT5 inhibitory activity.
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- Chemical modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2h-benzo[d]imidazole-2-one scaffold as a novel NLRP3 inhibitor
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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.
- Bertinaria, Massimo,Blua, Federica,Boscaro, Valentina,Gallicchio, Margherita,Gastaldi, Simone,Gianquinto, Eleonora,Giorgis, Marta,Macdonald, Justin A.,Marini, Elisabetta,Sandall, Christina F.,Spyrakis, Francesca
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- 1,3,4-OXADIAZOLE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to 1,3,4-oxadiazole derivative compounds having a histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, a use thereof in preparation of a medicament, a pharmaceutical composition comprising the same, a therapeutic method using the composition, and a method for preparing the same, and the 1,3,4-oxadiazole derivative compounds are represented by a following chemical formula (I).
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Page/Page column 102-103
(2020/12/11)
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- Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias
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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.
- 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.
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p. 8895 - 8907
(2018/10/05)
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- The preparation method of the deuterium generation of Mauzy is special
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The invention discloses a preparation method of deuterated pimozide. The pimozide-d4 is synthesized from 4-bromopentafluorobenzene-d4 through eight steps. The provided preparation method has the advantages of reasonable technological design, simple operation, easy product separation and purification, easily-available raw materials, high yield, and high purity. The isotope abundance of the obtained target product is high. The prepared stable isotope-labeled pimozide-d4 can be well applied to clinical pharmacokinetics researches, so people can acknowledge the metabolism process and action mechanism of pimozide in human body more precisely and conveniently, and thus the deuterated pimozide has an important application value.
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- Rapid construction of imidazopyridines from ortho-haloaminopyridines
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A practical strategy for the preparation of imidazopyridine derivatives from ortho-haloaminopyridines utilizing a two-step C-N coupling/cyclization reaction sequence has been developed. This procedure provides rapid and efficient access to many medicinally interesting imidazopyridine compounds and related imidazopyrazine/purine heterocycles.
- Li, Chaomin,Chen, Lily,Steinhuebel, Dietrich,Goodman, Andrew
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supporting information
p. 2708 - 2712
(2016/06/09)
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- BENZIMIDAZOLE DERIVATIVES AS RLK and ITK INHIBITORS
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The present disclosure is directed to certain inhibitors of RLK and ITK of formula (I), pharmaceutical compositions comprising such compounds, and method of treating diseases mediated by inhibition of RLK and ITK.
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- BENZIMIDAZOLE DERIVATIVES AS ITK INHIBITORS
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The present disclosure is directed to certain inhibitors of kinases such as ITK, BLK, BMX, BTK, JAK3, TEC, TXK, HER2 (ERBB2), or HER4 (ERBB4), in particular ITK, pharmaceutical compositions comprising such compounds, and method of treating diseases mediated by such kinases.
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- Non-benzimidazole containing inhibitors of respiratory syncytial virus
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Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.
- Pryde, David C.,Tran, Thien-Duc,Gardner, Iain,Bright, Helen,Stupple, Paul,Galan, Sebastien,Alsop, Liam,Watson, Lesa,Middleton, Donald S.,Dayal, Satish,Platts, Michelle,Murray, Edward J.,Parkinson, Tanya,Webster, Robert
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p. 827 - 833
(2013/03/13)
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- Concise and simple synthesis of M1 allosteric agonist TBPB
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A concise and simple synthesis of M1 allosteric agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d] imidazol-2(3H)-one (TBPB) using economical and commercially available orthophenylenediamine (O-PDA) and Boc piperidone has been described. The disclosed scheme allows synthesizing more analogs that were otherwise difficult to prepare with the original method. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Rasheed, Mohammed Abdul,Shaik, Nagul Meera,Nirogi, Ramakrishna
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p. 1796 - 1801
(2013/05/21)
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- PIPERIDINYL SUBSTITUTED 1,3-DIHYDRO-BENZOIMIDAZOL-2-YLIDENEAMINE DERIVATIVES
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The invention relates to new derivatives of formula (I) wherein the substituents are as defined in the specification; to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicament; such derivatives for the treatment of one or more IGF-1R mediated disorders or diseases
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Page/Page column 50-51
(2012/01/06)
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- Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents
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The lead optimization of a series of N-substituted benzimidazole CXCR4 antagonists is described. Side chain modifications and stereochemical optimization led to substantial improvements in potency and protein shift to afford compounds with low nanomolar a
- Miller, John F.,Turner, Elizabeth M.,Gudmundsson, Kristjan S.,Jenkinson, Stephen,Spaltenstein, Andrew,Thomson, Michael,Wheelan, Pat
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scheme or table
p. 2125 - 2128
(2010/06/13)
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- Rapid access towards follow-up NOP receptor agonists using a knowledge based approach
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A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement
- Palin, Ronald,Clark, John K.,Evans, Louise,Feilden, Helen,Fletcher, Dan,Hamilton, Niall M.,Houghton, Andrea K.,Jones, Philip S.,McArthur, Duncan,Montgomery, Brian,Ratcliffe, Paul D.,Smith, Alasdair R.C.,Sutherland, Aaron,Weston, Mark A.,Wishart, Grant
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scheme or table
p. 6441 - 6446
(2010/05/02)
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- Compounds with antiparasitic activity, applications thereof to the treatment of infectious diseases caused by apicomplexans
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The Invention relates to compounds having an antiparasitic activity, and to their use as a drug, in particular as a drug for the prevention and/or treatment of parasitic diseases caused by apicomplexans. The invention also relates to pharmaceutical compositions containing those compounds.
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Page/Page column 25
(2009/01/20)
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- CHEMICAL COMPOUNDS
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The present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind specifically to the chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 and/or CCR5 of a target cell.
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Page/Page column 72
(2010/10/20)
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- Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase
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Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, ne
- Rückle, Thomas,Biamonte, Marco,Grippi-Vallotton, Tania,Arkinstall, Steve,Cambet, Yves,Camps, Montserrat,Chabert, Christian,Church, Dennis J.,Halazy, Serge,Jiang, Xuliang,Martinou, Isabelle,Nichols, Anthony,Sauer, Wolfgang,Gotteland, Jean-Pierre
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p. 6921 - 6934
(2007/10/03)
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- 1,3-Dihydro-2,1,3-benzothiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3- benzothidiazin-2,2-diones as ligands for the NOP receptor
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A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhi
- Goehring, R. Richard,Whitehead, John F.W.,Brown,Islam, Khondaker,Wen, Xin,Zhou, Xiaoming,Chen, Zhengming,Valenzano, Kenneth J.,Miller, Wendy S.,Shan, Shen,Kyle, Donald J.
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p. 5045 - 5050
(2007/10/03)
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- Synthesis of (1-substituted piperidin-4-yl)-1H-benzimidazoles and (1-substituted piperidin-4-yl)-3,4-dihydroquinazolines as possible antihypertensive agents
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Structural modifications of 4-piperidylbenzimidazolinones (I) by replacing the benzimidazolinone group with other heterocycles (2-cyanoamino, 2-ethoxy, and 2-methylbenzimidazole and 2-cyanoamino-3,4-dihydroquinazoline) has been made and a number of new pi
- Obase,Takai,Teranishi,Nakamizo
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p. 565 - 573
(2007/10/02)
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