3735-92-0Relevant articles and documents
Holloway,Gitlitz
, p. 2659,2660 (1967)
Discovery of 5-chloro- N 2-[(1 S)-1-(5-fluoropyrimidin-2-yl) ethyl]- N 4-(5-methyl-1 H -pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the jak/stat pathway
Ioannidis, Stephanos,Lamb, Michelle L.,Wang, Tao,Almeida, Lynsie,Block, Michael H.,Davies, Audrey M.,Peng, Bo,Su, Mei,Zhang, Hai-Jun,Hoffmann, Ethan,Rivard, Caroline,Green, Isabelle,Howard, Tina,Pollard, Hannah,Read, Jon,Alimzhanov, Marat,Bebernitz, Geraldine,Bell, Kirsten,Ye, Minwei,Huszar, Dennis,Zinda, Michael
experimental part, p. 262 - 276 (2011/03/20)
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
Medium effect on the rotational barrier of carbamates and its sulfur congeners
Pontes, Rodrigo M.,Basso, Ernani A.,Dos Santos, Francisco P.
, p. 1901 - 1911 (2007/10/03)
The solvent effect on rotation about the conjugated C-N bond has been studied for methyl N,N-dimethylcarbamate (1), S-methyl N,N-dimethylthiocarbamate (2), O-methyl N,N-dimethylthiocarbamate (3), and methyl N,N- dimethyldithiocarbamate (4). The present investigation included experimental determination of activation parameters (ΔH?, ΔS?, and ΔG?) combined with theoretical calculations via both quantum and classical approaches. Rotational barriers were measured through dynamic NMR experiments in solvents of varied polarity and proton donor ability. In the less polar solvents, the values were 15.3 ± 0.5 (CS2), 14.0 ± 1.1 (CS2), 17.5 ± 0.4 (CCl4), and 14.6 ± 0.5 kcal/mol (CCl4) for 1, 2, 3, and 4, respectively. Upon changing to an aqueous solution, the greatest variations occurred for 2 and 4, whereas for 1 and 3, there was no observable effect. Quantum chemical calculations at the HF/6-311+G(2d,p) and B3LYP/6-311+G(2d,p) levels, with the inclusion of solvation effects via the isodensity polarizable continuum model (IPCM), correctly reproduced the experimentally observed trends but failed to account for some of the measured rotational barrier's magnitudes. Hydrogen-bonding effects were included by performing molecular dynamic simulations. For these latter calculations, it was necessary to parametrize the force field against energies of water-solute complexes calculated at B3LYP/6-31+G-(d,p). Through the results of radial distribution functions, solution rotational barriers could be calculated, presenting good agreement with experimental determinations and revealing the role of hydrogen bonding. Interestingly, only for 2, the rotational barrier is predicted to increase as a result of complexation with water. For the remaining compounds, hydrogen bonding causes the barrier to decrease, contrasting with most of the molecular systems studied up to now.
