111300-06-2Relevant academic research and scientific papers
Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase
Chen, Ting,Takrouri, Khuloud,Hee-Hwang, Sung,Rana, Sandeep,Yefidoff-Freedman, Revital,Halperin, Jose,Natarajan, Amarnath,Morisseau, Christophe,Hammock, Bruce,Chorev, Michael,Aktas, Bertal H.
, p. 9457 - 9470 (2013)
Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as β-thalassemia. We previously identified N,N′-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ～1900 member N,N′-disubstituted urea library in the surrogate eIF2α phosphorylation assay, identifying N-aryl,N′-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N′-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N′- cyclohexylphenoxyureas in the surrogate eIF2α phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.
Inhibition of serine and proline racemases by substrate-product analogues
Harty, Matthew,Nagar, Mitesh,Atkinson, Logan,Legay, Christina M.,Derksen, Darren J.,Bearne, Stephen L.
, p. 390 - 393 (2014)
d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (K i = 167 ± 21 mM, Ki′ = 661 ± 81 mM, cf. Km = 19 ± 2 mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5 mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki = 111 ± 15 mM, cf. Km = 5.7 ± 0.5 mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.
ALKYNYL QUINAZOLINE COMPOUNDS
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Paragraph 1094, (2021/02/19)
The present disclosure relates to compounds of Formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.
Trans-Selective and Switchable Arene Hydrogenation of Phenol Derivatives
Bergander, Klaus,Glorius, Frank,Heusler, Arne,Wollenburg, Marco
, p. 11365 - 11370 (2020/11/24)
A trans-selective arene hydrogenation of abundant phenol derivatives catalyzed by a commercially available heterogeneous palladium catalyst is reported. The described method tolerates a variety of functional groups and provides access to a broad scope of trans-configurated cyclohexanols as potential building blocks for life sciences and beyond in a one-step procedure. The transformation is strategically important because arene hydrogenation preferentially delivers the opposite cis-isomers. The diastereoselectivity of the phenol hydrogenation can be switched to the cis-isomers by employing rhodium-based catalysts. Moreover, a protocol for the chemoselective hydrogenation of phenols to cyclohexanones was developed.
Catalytic Transfer Hydrogenation of Arenes and Heteroarenes
Gelis, Coralie,Heusler, Arne,Nairoukh, Zackaria,Glorius, Frank
supporting information, p. 14090 - 14094 (2020/10/19)
Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3-dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.
TEAD INHIBITORS AND USES THEREOF
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Paragraph 00465; 00701, (2020/12/11)
The present invention provides compounds, compositions thereof, and methods of using the same.
Photoinduced Deoxygenative Borylations of Aliphatic Alcohols
Wu, Jingjing,B?r, Robin M.,Guo, Lin,Noble, Adam,Aggarwal, Varinder K.
supporting information, p. 18830 - 18834 (2019/11/22)
A photochemical method for converting aliphatic alcohols into boronic esters is described. Preactivation of the alcohol as a 2-iodophenyl-thionocarbonate enables a novel Barton–McCombie-type radical deoxygenation that proceeds efficiently with visible light irradiation and without the requirement for a photocatalyst, a radical initiator, or tin or silicon hydrides. The resultant alkyl radical is intercepted by bis(catecholato)diboron, furnishing boronic esters from a diverse range of structurally complex alcohols.
INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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Page/Page column 102; 122, (2018/06/30)
The present disclosure is directed to compounds of Formula (I) and methods of their use and preparation, as well as compositions comprising compounds of Formula (I).
UREA DERIVATIVE AND USE THEREFOR
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Paragraph 0190, (2018/07/29)
The purpose of the present invention is to provide a compound with inhibitory activity on Discoidin Domain Receptor 1. The present invention provides a urea derivative represented by the formula below or a pharmaceutically acceptable salt thereof.
Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same
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Paragraph 0270-0273, (2018/05/17)
The present invention relates to a novel autotaxin inhibitor compound for preventing and treating disease or symptoms due to an increase in concentration of lysophosphatidic acid or activation of autotaxin. The present invention further relates to a pharmaceutical composition containing the same. The novel compound of the present invention is an autotaxin inhibitor which inhibits production of lysophosphatidic acid, and thus is useful for treating or preventing cardiovascular disease, cancer, metabolic disease, kidney disease, liver disease, inflammatory diseases, nervous disease, respiratory disease, desmoid disease, eye disease, cholestatic symptoms, other types of chronic pruritus or acute, or chronic rejection of transplanted organs.COPYRIGHT KIPO 2017
