- An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis
-
Deregulation of protein synthesis is a common event in cancer. As MAPK-interacting kinases (Mnks) play critical roles in regulation of protein synthesis, they have emerged as novel anti-cancer targets. Mnks phosphorylate eukaryotic initiation factor 4E (eIF4E) and promote eIF4E-mediated oncogenic activity. Given that the kinase activity of Mnks is essential for oncogenesis but is dispensable for normal development, the discovery of potent and selective pharmacological Mnk inhibitors provides pharmacological target validation and offers a new strategy for cancer treatment. Herein, comprehensive in silico screening approaches were deployed, and three thieno[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives were identified as hit compounds. Further chemical modification of thieno[2,3-d]pyrimidine derivative 3 has given rise to a series of highly potent Mnk2 inhibitors that could be potential leads for the treatment of acute myeloid leukemia.
- Teo, Theodosia,Yang, Yuchao,Yu, Mingfeng,Basnet, Sunita K.C.,Gillam, Todd,Hou, Jinqiang,Schmid, Raffaella M.,Kumarasiri, Malika,Diab, Sarah,Albrecht, Hugo,Sykes, Matthew J.,Wang, Shudong
-
p. 539 - 550
(2015/10/12)
-
- PROTEIN KINASE C INHIBITORS AND USES THEREOF
-
This disclosure concerns compounds which are useful as inhibitors of protein kinase C (PKC) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC. This disclosure also relates to ph
- -
-
-
- Piperazine compounds and medicinal use thereof
-
The present invention relates to a piperazine compound of the formula wherein R1and R2are each hydrogen, halogen, lower alkyl, lower alkoxy, amino, substituted amino, nitro, hydroxy or cyano, R3, R4and R5are each hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, substituted amino or hydroxy, R6and R7are each hydrogen, lower alkyl, lower alkyl substituted by halogen, aralkyl, acyl or lower acyl substituted by halogen, R8and R9are each hydrogen or lower alkyl, Y is lower alkylene and the like, and ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl, a pharmaceutically acceptable salt thereof and pharmaceutical agents containing these compounds. The compound of the present invention has superior TNF-α production inhibitory effect and/or IL-10 production promoting effect, and, since it is free of or shows only strikingly reduced expression of an effect on the central nervous system, the compound is useful as a highly safe and superior TNF-α production inhibitor an/or IL-10 production promoter and is useful as an agent for the prophylaxis or treatment of various diseases caused by abnormal TNF-α production, diseases curable with IL-10, such as chronic inflammatory diseases, acute inflammatory diseases, inflammatory diseases due to infection, autoimmune diseases, allergic diseases, and TNF-α mediated diseases.
- -
-
-
- Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT(1A), and adrenergic α1 receptors
-
New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5- HT(1A), and α1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1- methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.
- Reitz, Allen B.,Baxter, Ellen W.,Codd, Ellen E.,Davis, Coralie B.,Jordan, Alfonzo D.,Maryanoff, Bruce E.,Maryanoff, Cynthia A.,McDonnell, Mark E.,Powell, Eugene T.,Renzi, Michael J.,Schott, Mary R.,Scott, Malcolm K.,Shank, Richard P.,Vaught, Jeffry L.
-
p. 1997 - 2009
(2007/10/03)
-
- 4-ARYLPIPERAZINES AND 4-ARYLPIPERIDINES
-
Compounds of the general formula I: STR1 are disclosed as novel antipsychotic agents.
- -
-
-