- Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics**
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Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure-based design of a new class of alanine-containing 3-arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds.
- Sutherland, Mathew,Li, Alice,Kaghad, Anissa,Panagopoulos, Dimitrios,Li, Fengling,Szewczyk, Magdalena,Smil, David,Scholten, Cora,Bouché, Léa,Stellfeld, Timo,Arrowsmith, Cheryl H.,Barsyte, Dalia,Vedadi, Masoud,Hartung, Ingo V.,Steuber, Holger,Britton, Robert,Santhakumar, Vijayaratnam
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supporting information
p. 1116 - 1125
(2021/03/08)
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- BIARYL PYRAZOLES AS NRF2 REGULATORS
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The present invention relates to biaryl pyrazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators.
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Page/Page column 410; 411
(2017/08/01)
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- FUSED PYRAZINE DERIVATIVES AS KINASE INHIBITORS
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A series of quinoxaline derivatives, and analogues thereof, which are functionalised further by a substituted phenyl or pyridinyl moiety, being selective inhibitors of PO kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 45
(2010/06/11)
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- Synthesis and structure-activity relationships of long-acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups
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A series of saligenin alkoxyalkylphenylsulfonamide β2 adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the paraand the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the β2-receptor is presented.
- Procopiou, Panayiotis A.,Barrett, Victoria J.,Bevan, Nicola J.,Biggadike, Keith,Butchers, Peter R.,Coe, Diane M.,Conroy, Richard,Edney, Dean D.,Field, Rita N.,Ford, Alison J.,Guntrip, Stephen B.,Looker, Brian E.,McLay, Iain M.,Monteith, Michael J.,Morrison, Valerie S.,Mutch, Peter J.,Richards, Stephen A.,Sasse, Rosemary,Smith, Claire E.
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supporting information; experimental part
p. 2280 - 2288
(2010/03/25)
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- Synthesis and PKCθ inhibitory activity of a series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles
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A series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles were prepared and evaluated as PKCθ inhibitors. Optimization resulted in the identification of compound 15 with an IC50 value 0.44 nM for the inhibition of PKCθ with 150-fold select
- Shim, Jaechul,Eid, Clark,Lee, Julie,Liu, Erica,Chaudhary, Divya,Boschelli, Diane H.
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scheme or table
p. 6575 - 6577
(2010/06/12)
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- New phenylpyridylpiperazine compounds
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A compound selected from those of formula (I): [image] wherein: X represents a C(O) or SO2 group, R1 represents an aryl group or a group NR3R4 wherein R3 and R4 are as defined in the description, R2 represents an alkyl, (C3-C8)cycloalkyl or (C3-C8)cycloalkyl-(C1-C6)alkyl group, its isomers, and addition salts thereof, and medicinal products containing the same which are useful in treating conditions treatable by antagonists of type H3 central histamine receptors.
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Page/Page column 7
(2008/06/13)
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