173089-81-1Relevant articles and documents
Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
Buijs, Ned,Campagna, Roberto,Emanuelli, Monica,Gao, Yongzhi,Innocenti, Paolo,Jespers, Willem,Martin, Nathaniel I.,Parsons, Richard B.,Sartini, Davide,Van Haren, Matthijs J.,Van Westen, Gerard J. P.,Zhang, Yurui,Gutiérrez-De-Terán, Hugo
, p. 12938 - 12963 (2021/09/11)
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER
-
, (2021/01/29)
A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.
Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity
Aoyagi, Atsushi,Conrad, Jay,Droege, Daniel G.,Elepano, Manuel,Grandjean, Jean-Marc M.,Hirano, Shimpei,Hirasawa, Makoto,Hirouchi, Masakazu,Inoue, Masahiro,Jiu, Alexander Y.,Lee, Joanne,Murakami, Ryo,Ohyama, Takao,Olson, Steven H.,Paras, Nick A.,Prusiner, Stanley B.,Sasaki, Koji,Tang, Benjamin C.,Vaz, Roy J.,West, John W.
supporting information, (2020/02/13)
Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC50 value of 390 nM and 0.04 Kp,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; Kp,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.
Palladium-catalyzed synthesis of aldehydes from aryl halides and tert-butyl isocyanide using formate salts as hydride donors
Zhang, Ying,Jiang, Xiao,Wang, Jin-Mei,Chen, Jing-Lei,Zhu, Yong-Ming
, p. 17060 - 17063 (2015/03/30)
An efficient one-pot palladium-catalyzed hydroformylation of aryl halides to produce aromatic aldehydes has been achieved, employing tert-butyl isocyanide as a C1 resource and formate salt as a hydride donor without any additional bases. Characterized by its mild reaction conditions, easy operation and lower toxicity, this reaction can tolerate a wide array of functional groups with moderate to excellent yields.
HETEROCYCLIC MODULATORS OF PKB
-
Page/Page column 100-101, (2009/03/07)
The invention relates to heterocyclic compounds of Formula I and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein Formula (I). The invention also relates to the therapeutic use of such compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
Kinase inhibitors
-
, (2008/06/13)
Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
Kinase inhibitors
-
Page/Page column 68, (2010/01/31)
Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
