BMS-066

The structural characterization of several polymorphic forms of a compound allow the interplay between molecular conformation and intermolecular interactions to be studied, which can contribute to the development of strategies for the rational preparation of materials with desirable properties and the tailoring of intermolecular interactions to produce solids with predictable characteristics of interest in crystal engineering. The crystal structures of two new polymorphs of 5,6-dimethyl-2-(pyridin-2-yl)-1-[(pyridin-2-yl)methyl]-1H-benzimidazole, C20H18N4, are reported. The previously reported polymorph, (1) [Geiger & DeStefano (2014).Acta Cryst.E70, o365], exhibits the space groupC2/c, whereas polymorphs (2) and (3) presented here are in thePnmaandP\overline{1} space groups, respectively. The molecular structures of the three forms differ in their orientations of the 2-(pyridin-2-yl)- and 1-[(pyridin-2-yl)methyl]- substituents. Density functional theory (DFT) calculations show that the relative energies of the molecule in the three conformations follows the order (1) < (2) < (3), with a spread of 10.6 kJ mol−1. An analysis of the Hirshfeld surfaces shows that the three polymorphs exhibit intermolecular C—H...N interactions, which can be classified into six types. Based on DFT calculations involving pairs of molecules having the observed interactions, the C—H...N energy in the systems explored is approximately −11.2 to −14.4 kJ mol−1.

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.