- Structure–Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7
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SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small-molecule inhibitors have been reported that target SETD7, the most potent being (R)-PFI-2. Herein we report structure–activity relationship studies on (R)-PFI-2 and its analogues. A library of 29 structural analogues of (R)-PFI-2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)-PFI-2′s NH2+ group and SETD7′s Asp256 and His252 residue, respectively.
- Lenstra, Danny C.,Damen, Eddy,Leenders, Ruben G. G.,Blaauw, Richard H.,Rutjes, Floris P. J. T.,Wegert, Anita,Mecinovi?, Jasmin
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supporting information
p. 1405 - 1413
(2018/07/29)
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- Discovery of pyrrolopyrimidine inhibitors of Akt
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The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
- Blake, James F.,Kallan, Nicholas C.,Xiao, Dengming,Xu, Rui,Bencsik, Josef R.,Skelton, Nicholas J.,Spencer, Keith L.,Mitchell, Ian S.,Woessner, Richard D.,Gloor, Susan L.,Risom, Tyler,Gross, Stefan D.,Martinson, Matthew,Morales, Tony H.,Vigers, Guy P.A.,Brandhuber, Barbara J.
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scheme or table
p. 5607 - 5612
(2010/11/17)
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- N-acylamino acid amide compounds and intermediates for preparation thereof
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The present invention discloses the compound represented by the formula (I): wherein A represents the following formula (a-1) or the following formula (a-2): B represents the following formula (b): (wherein the symbols are each as defined in the specification) or a pharmaceutically acceptable salts thereof, and intermediates for the preparation thereof, which have excellent platelet aggregation inhibitory activity and other properties and useful as prophylactic or therapeutic agents for diseases associated with a fibrinogen receptor, thrombosis, infarction and the like.
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- Studies of Neurokinin Antagonists. 4. Synthesis and Structure-Activity Relationships of Novel Dipeptide Substance P Antagonists: N2--L-prolyl>-N-methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and Its Related Compounds
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As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-2-(1H-indol-3-ylcarbonyl)-L-lysyl>-N-methyl-N-(phenylmethyl)-L-phenylalaninamide (2b).The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in SP binding assay using guinea pig lung membranes.Next we modified the 1H-indol-3-ylcarbonyl part in 3h.Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity.Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
- Hagiwara, Daijiro,Miyake, Hiroshi,Igari, Norihiro,Karino, Masako,Maeda, Yasue,et al.
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p. 2090 - 2099
(2007/10/02)
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