Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.

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.

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHßE.

We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki-Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of the elusive CD fragment of the Erythrina alkaloid DHßE. Preliminary pharmacological evaluations support the notion that the key pharmacophores of DHßE are located in the A and B rings.

In situ generation of the Ohira-Bestmann reagent from stable sulfonyl azide: scalable synthesis of alkynes from aldehydes.

We report an improved method for in situ generation of the Ohira-Bestmann reagent. Using the recently reported bench-stable imidazole-1-sulfonyl azide as diazotransfer reagent, this new method represents a scalable and convenient approach for the transformation of aldehydes into terminal alkynes. The method features an easier workup compared to the existing in situ protocol due to increased aqueous solubility of waste products.

Synthesis and Pharmacological Evaluation of DHßE Analogues as Neuronal Nicotinic Acetylcholine Receptor Antagonists.

Dihydro-ß-erythroidine (DHßE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4ß2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHßE in complex with an ACh binding protein, we detail the design, synthesis, and pharmacological characterization of a series of DHßE analogues in which two of the four rings in the natural product has been excluded. We found that the direct analogue of DHßE maintains affinity for the α4ß2-subtype, but further modifications of the simplified analogues were detrimental to their activities on the nAChRs.