3574-54-7Relevant articles and documents
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.
Kinetics and mechanism of acid-catalyzed hydration of 5-hydroxymethyl- and 5-phenoxymethylnorborn-2-enes
Lajunen, Martti,Latva-Nirva, Esa
, p. 719 - 723 (2007/10/03)
The disappearance rate constants for exo- and endo-5-hydroxymethylnorborn-2-enes (3 and 4) and exo- and endo-5-phenoxymethylnorborn-2-enes (5 and 6) were measured in aqueous perchloric acid by a capillary GC method at different temperatures and acid concentrations. The rate constants, activation parameters, excess acidity plots and products (for 3 and 4 only) are in agreement with the rate-determining protonation of the double bond (AdE2 mechanism). No proof of endo protonation of the double bond via the protonated endo-5-CH2OH group was obtained. The excess acidity plots were corrected according to the partial protonation of the hydroxylic or ether oxygen atom. In the case of 3 and 4, the slope parameter m?, indicative of the transition state, decreases slightly with increasing temperature, the intercept parameter log (ko/M-1s-1) depends reasonably on the temperature, and the protonation site parameters of the hydroxymethyl group, m′ and pKS′H+, are temperature-independent. The corresponding parameters for 5 and 6 at 303 K are normal except the peculiar pKS′H+ values, ca. -2.5.
