- Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity
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The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
- Mahy, William,Patel, Mikesh,Steadman, David,Woodward, Hannah L.,Atkinson, Benjamin N.,Svensson, Fredrik,Willis, Nicky J.,Flint, Alister,Papatheodorou, Dimitra,Zhao, Yuguang,Vecchia, Luca,Ruza, Reinis R.,Hillier, James,Frew, Sarah,Monaghan, Amy,Costa, Artur,Bictash, Magda,Walter, Magnus W.,Jones, E. Yvonne,Fish, Paul V.
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p. 9464 - 9483
(2020/10/19)
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- An efficient and convenient synthesis of 1,2,3-trisubstituted pyrroles via iodocyclization from ethyl acetoacetate
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A novel and efficient methodology for the synthesis of 1,2,3-trisubstituted pyrroles by one-pot two-step reaction has been developed. The iodocyclization of a series of β-enamino esters followed by dehydroiodination, led to the formation of corresponding pyrroles. This approach provides an easy access to a wide range of 1,2,3-trisubstituted pyrroles.
- Xu, Pengfei,Huang, Kunzhu,Liu, Zhiguo,Zhou, Ming,Zeng, Wenbin
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supporting information
p. 2929 - 2933
(2013/06/27)
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- PYRROLO- AND THIAZOLO-PYRIDINE COMPOUNDS, AND METHODS OF USE THEREOF
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The present invention relates to novel compounds capable of modulating the stability and/or activity of hypoxia inducible factor (HIF).
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Page/Page column 24
(2008/06/13)
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- A two step synthesis of 1,2,3-substituted pyrroles
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A method for preparing substituted pyrroles 3a-g in two steps from dihydrofurans 2a-b which were synthesized from α,α'-diazocarbonyl derivatives 1a-b was developed. The relevance of this research work lies in the easiness of preparing the substituted dihydrofurans and transforming them into pyrroles under mild conditions.
- Cunha, Anna C.,Pereira, Leticia O. R.,De Souza, Rodrigo O. P.,De Souza, Maria Cecilia B. V.,Ferreira, Vitor F.
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p. 3215 - 3226
(2007/10/03)
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- Unsaturated Sulfoxides in Organic Synthesis: a New General Pyrrole Synthesis
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Pyrroles have been efficiently synthesised by a three-step reaction sequence.Michael addition of keto esters onto phenyl vinyl sulfoxide followed by Pummerer rearrangement gave the cyclic key intermediate 3.Mercury(II) salt induced carbon-sulfur bond clea
- Chan, Wing Hong,Lee, Albert W. M.,Lee, Ka Ming,Lee, Tin Yau
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p. 2355 - 2356
(2007/10/02)
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