13137-31-0Relevant academic research and scientific papers
Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity
Hansen, Bettina Borreschmidt,Jepsen, Tue Heesgaard,Larsen, Mogens,Sindet, Rikke,Vifian, Thomas,Burhardt, Mia N?rreskov,Larsen, Jens,Seitzberg, Jimmi Gerner,Carnerup, Martin A.,Jerre, Anders,M?lck, Christina,Lovato, Paola,Rai, Sanjay,Nasipireddy, Venkatarathnam Reddy,Ritzén, Andreas
, p. 7008 - 7032 (2020/07/28)
Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.
Optical and Neutron Inelastic Scattering Study of 2-Methylnorbornanes
Brunel, Yvon,Coulombeau, Christian,Coulombeau, Christiane,Jobic, Herve
, p. 937 - 943 (2007/10/02)
We have measured the infrared, Raman, and neutron vibrational spectra of the 2-methylnorbornanes with a CH3 or CD3 methyl group in the exo or endo position.A normal coordinate analysis has been carried out.The torsional modes of the methyl group are assigned at 240 and 235 cm-1 for the hydrogenated exo and endo isomers, respectively.The corresponding barrier is 15.2 +/- 0.2 kJ mol-1.The calculated neutron intensities are in good agreement with the experimental data.The frequencies are used for the determination of the thermodynamic contribution to the standard free energy difference.
Stereochemistry of Addition of the Allyl Grignard Reagent to Hydroxybicyclohept-2-enes
Richey, Herman G.,Wilkins, Cletus W.
, p. 5027 - 5036 (2007/10/02)
Reactions of syn-bicyclohept-2-en-7-ol with an excess of allylmagnesium chloride in tetrahydrofuran or of allylmagnesium bromide in diethyl ether furnish an addition product shown to be 2-exo-allyl-syn-bicycloheptan-7-ol.Reactions of endo-bicyclohept-5-en-2-ol with the same reagents and with diallylmagnesium in ether furnish a compound shown to be 5-endo-allyl-endo-bicycloheptan-2-ol.A metalated hydroxyl group must play an active role in facilitating these additions since they proceed more rapidly than addition to the parent hydrocarbon,bicyclohept-2-ene, which furnishes 2-exo-allylbicycloheptane.They must also be considerably more rapid than additions to the epimeric alcohols (anti-bicyclohept-2-en-7-ol and exo-bicyclohept-5-en-2-ol) since no addition products were obtained from reactions with these alcohols.Attachment of the allyl group to the double bond of each bicycloheptenol from the side nearer the hydroxyl group suggests that at the time of addition the allyl is associated with the metalated hydroxyl group.
