A crosslinked polymer skin barrier film for moderate to severe atopic dermatitis: A pilot study in adults.

Background: Occlusive treatments are a mainstay in atopic dermatitis (AD) management but may not be well tolerated or lack compliance. A comfortable, semiocclusive, artificial skin barrier that is well tolerated, provides protection, and reduces water loss is needed.

Objective: To evaluate the potential tolerability and therapeutic benefits of a crosslinked polymer layer (XPL) in adults with AD.

Thiophene carboxamide inhibitors of JAK2 as potential treatments for myleoproliferative neoplasms.

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization.

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics.

Efficacious intermittent dosing of a novel JAK2 inhibitor in mouse models of polycythemia vera.

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition.

The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead.

This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.