- An Angle on MK2 Inhibition—Optimization and Evaluation of Prevention of Activation Inhibitors
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The mitogen-activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen-activated protein kinase-activated protein kinase 2 (MK2) rather than mitogen- and stress-activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole 9 (2-(3′-(2-amino-2-oxoethyl)-[1,1′-biphenyl]-3-yl)-N-(5-(N,N-dimethylsulfamoyl)-2-methylphenyl)-1-propyl-1H-imidazole-5-carboxamide) and the orally bioavailable imidazole 18 (3-methyl-N-(2-methyl-5-sulfamoylphenyl)-2-(o-tolyl)imidazole-4-carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although 9 and 18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway.
- Hedstr?m, Ulf,Norberg, Monica,Evertsson, Emma,Lever, Sarah R.,Munck af Rosensch?ld, Magnus,L?nn, Hans,Bold, Peter,K?ck, Helena,Berntsson, Pia,Vinblad, Johanna,Liu, Jianming,Welinder, Anette,Karlsson, Johan,Snijder, Arjan,Pardali, Katerina,Andersson, Ulf,Davis, Andrew M.,Mogemark, Mickael
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supporting information
p. 1701 - 1709
(2019/08/21)
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- As opioid receptor antagonists or inverse agonists of the novel compounds
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Novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, pharmaceutical compositions containing them, to processes for their preparation.
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Paragraph 0396; 0397
(2016/10/08)
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- NOVEL COMPOUNDS AS ANTAGONISTS OR INVERSE AGONISTS AT OPIOID RECEPTORS
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Novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, pharmaceutical compositions containing them, to processes for their preparation.
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- Discovery of biaryl inhibitors of H+/K+ ATPase
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We report the identification of a novel biaryl template for H+/K+ ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
- Garton, Neil,Bailey, Nick,Bamford, Mark,Demont, Emmanuel,Farre-Gutierrez, Irene,Hutley, Gail,Bravi, Gianpaolo,Pickering, Paula
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scheme or table
p. 1049 - 1054
(2010/06/12)
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- METHOD OF TREATMENT USING NOVEL ANTAGONISTS OR INVERSE AGONISTS AT OPIOID RECEPTORS
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A method of treatment using pharmaceutical compositions containing novel antagonists or inverse agonists at opioid receptors for the treatment of binge eating disorder, anorexia nervosa, bulimia nervosa, excess drug or alcohol use, or eating disorder not otherwise specified.
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