119768-44-4Relevant articles and documents
Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase
Zhang, Rong,McIntyre, Patrick J.,Collins, Patrick M.,Foley, Daniel J.,Arter, Christopher,von Delft, Frank,Bayliss, Richard,Warriner, Stuart,Nelson, Adam
, p. 6831 - 6839 (2019)
Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3-rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.
Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists
Roever,Adams,Benardeau,Bentley,Bickerdike,Bourson,Cliffe,Coassolo,Davidson,Dourish,Hebeisen,Kennett,Knight,Malcolm,Mattei,Misra,Mizrahi,Muller,Porter,Richter,Taylor,Vickers
, p. 3604 - 3608 (2005)
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a- hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT2 receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT2C receptor agonists.
Hexahydro-1 H -Isoindolinone-Like Scaffolds from Electronically Deactivated and Sterically Hindered Dienes: Synthesis in the Context of Muironolide A
Olson, Christopher A.,Shaner, Courtnay E.,Roche, Sydney C.,Ferrence, Gregory M.,Mitchell, T. Andrew
, p. 2756 - 2766 (2015)
Initial synthetic efforts toward muironolide A based upon an intramolecular Diels-Alder strategy were hampered by a conjugate reduction rather than the desired half-reduction. An intermolecular Diels-Alder strategy was initiated that utilized electronically deactivated and sterically hindered dienes. The [4+2] cycloadditions were successful, but only with highly reactive dipolarophiles such as N-phenylmaleimide and 4-phenyl-1,2,4-triazoline-3,5-dione thus establishing the scope of these dienes. Although limited, installation of the α,β-unsaturated lactam embedded in the hexahydro-1H-isoindolinone is noteworthy.
Hydrogen-Bonding-Driven Enantioselective Resolution against the Kazlauskas Rule To Afford γ-Amino Alcohols by Candida rugosa Lipase
Min, Bora,Park, Jeemin,Sim, Yong-Kyun,Jung, Suhyun,Kim, Seong-Ho,Song, Jae Kwang,Kim, Bum Tae,Park, Sang Youn,Yun, Jaesook,Park, Seongsoon,Lee, Hyuk
, p. 77 - 82 (2015)
Most lipases resolve secondary alcohols in accordance with the Kazlauskas rule to give the R enantiomers. In a similar manner to other lipases, Candida rugosa lipase (CRL) exhibits R enantioselectivity towards heptan-2-ol, although the enantiomeric ratio (E) is low (E=1.6). However, unexpected enantioselectivity (i.e., S enantioselectivity, E=58) of CRL towards 4-(tertbutoxycarbonylamino)butan-2-ol, which has a similar chain length to heptan-2-ol, has been observed. To develop a deeper understanding of the molecular basis for this unusual enantioselectivity, we have conducted a series of molecular modeling and substrate engineering experiments. The results of these computational and experimental analyses indicated that a hydrogen bond between the Ser450 residue and the nitrogen atom of the carbamate group is critical to stabilize the transition state of the S enantiomer.
The synthesis of a monoammonium derivative of fullerenopyrrolidine
Kutyreva,Shchupak,Karnatsevich,Bazyakina,Suvorova
, p. 1535 - 1536 (2005)
The Prato reaction was used to synthesize a monoammonium derivative of fullerenopyrrolidine.
Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells
Che, Jinxin,Chen, Binhui,Dong, Xiaowu,Gao, Anhui,Gao, Jian,Hu, Xiaobei,Hu, Yongzhou,Huang, Feng,Li, Jia,Qu, Bingxue,Xu, Gaoya,Ying, Huazhou,Zhang, Jianjun,Zhang, Mengmeng,Zhou, Yubo
, (2020)
The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development.
Substituted chiral diaryl macrocyclic compound as TRK inhibitors
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Paragraph 0080-0082, (2021/09/04)
The invention relates to a substituted chiral diaryl macrocyclic compound as a TRK inhibitor, and belongs to the technical field. The structure of the chiral diaryl macrocyclic compound is shown as a general formula (I), and the chiral diaryl macrocyclic
Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors
Cai, Shi,Guan, Dezhong,Li, Jinruo,Li, Pei,Xu, Lin,Zhang, Huibin,Zhao, Tong,Zhou, Jinpei
, (2021/11/11)
Tropomyosin receptor kinases (TRKA, TRKB, TRKC) are transmembrane receptor tyrosine kinases, which are respectively encoded by NTRK1, NTRK2, and NTRK3 genes. Herein, we reported the design, synthesis and Structure-Activity Relationship (SAR) investigation of a series of macrocyclic derivatives as new TRK inhibitors. Among these compounds, compound 9e exhibited strong kinase inhibitory activity (TRKG595R IC50 = 13.1 nM) and significant antiproliferative activity in the Ba/F3-LMNA-NTRK1 cell line (IC50 = 0.080 μM) and compound 9e has shown a better inhibitory effect (IC50 = 0.646 μM) than control drug LOXO-101 in Ba/F3-LMNA-NTRK1-G595R cell line. These results indicate that compound 9e is a potential TRK inhibitor for further investigation.
Bcl-2 INHIBITORS
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Paragraph 0249-0252, (2021/05/07)
Disclosed herein is a compound of Formula (I) for inhibiting Bcl-2 and treating disease associated with undesirable bcl-2 activity (Bcl-2 related diseases), a method of using the compounds disclosed herein for treating dysregulated apoptotic diseases incl
PYRIDINE COMPOUND SUBSTITUTED WITH AZOLE
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Paragraph 1051, (2020/07/07)
The present invention provides a compound represented by formula [I] shown below or a pharmaceutically acceptable salt thereof that has an inhibitory effect on 20-HETE producing enzyme. (in formula [I] above, the structure represented by formula [II] below: represents any of the structures represented by formula group [III] below: R1, R2, R3, and R4 independently represent a hydrogen atom, a fluorine atom, methyl, or the like, R5 represents any of the structures represented by formula group [IV]:
