Matthew W. Carson

An Intra/Intermolecular Suzuki Sequence to Benzopyridyloxepines Containing Geometrically Pure Exocyclic Tetrasubstituted Alkenes

A route to enable the preparation of 5-benzylidenyl-benzopyridyloxepine analogues was developed to continue our research in the field of nuclear hormone receptor modulators. The key steps are 1) a syn-stereoselective diboration of a tethered aryl alkyne; 2) an intramolecular Suzuki cross-coupling reaction, which forms in a stereo- and regiocontrolled fashion, the 5-exoalkylidenyl 7-membered ring imbedded within the core of the scaffold and; 3) an intermolecular Suzuki to furnish the final tetra-substituted olefinic benzopyridyloxepines.

Glucocorticoid receptor modulators informed by crystallography lead to a new rationale for receptor selectivity, function, and implications for structure-based design.

The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane sulfonamides, is a potent anti-inflammatory agent with selectivity for the GR versus other steroid receptors and a differentiated gene expression profile versus clinical glucocorticoids (lower GR transactivation with comparable transrepression). A stereospecific synthesis of this chiral molecule provides the unique topology needed for biological activity and structural biology. In vivo activity of 10 in acute and chronic models of inflammation is equivalent to prednisolone. The crystal structure of compound 10 within the GR ligand binding domain (LBD) unveils a novel binding conformation distinct from the classic model adopted by cognate ligands. The overall conformation of the GR LBD/10 complex provides a new basis for binding, selectivity, and anti-inflammatory activity and a path for further insights into structure-based ligand design.

HDX reveals unique fragment ligands for the vitamin D receptor

Modulation of the vitamin D receptor (VDR) with a ligand has the potential to be useful for the oral treatment of osteoporosis. One component of our lead generation strategy to identify synthetic ligands for VDR included a fragment based drug design approach. Screening of ligands in a VDR fluorescence polarization assay and a RXR/VDR conformation sensing assay resulted in the identification of multiple fragment hits (lean >0.30). These fragment scaffolds were subsequently evaluated for interaction with the VDR ligand binding domain using hydrogen-deuterium exchange (HDX) mass spectrometry. Significant protection of H/D exchange was observed for some fragments in helixes 3, 7, and 8 of the ligand binding domain, regions which are similar to those seen for the natural hormone VD3. The fragments appear to mimic the A-ring of VD3 thereby providing viable starting points for synthetic expansion.

Non-secosteroidal Ligands and Modulators

Publisher Summary This chapter provides an understanding of the identification, synthesis, biological, and pharmacological activities of non-secosteroidal ligands and modulators that are capable of binding in the traditional ligand-binding pocket of vitamin D receptor (VDR) to manipulate its physiologic and homeostatic functions in the various target tissues where it is expressed. The two main reasons for pursuing the design and development of novel non-secosteroidal ligands include the need for new and effective pharmacological agents for human disease treatment as well as the identification of research tools to further elucidate the biological function of vitamin D and VDR. The unique structural features of nonsecosteroidal ligands may afford advantageous properties that are inherently different from the liabilities surrounding 1α,25(OH)2D3 or its secosteroidal analogs. These properties include altered DBP binding, reduced 24-hydroxylase metabolism, distinct VDR modulating behavior, or enhanced pharmacokinetic and pharmacodynamic profiles. Five classes of compounds that can be chemically classified as non-secosteroids include molecules based on a diarylmethane chemical scaffold (LG190119, VDRM-2), C/D ring-modified scaffolds, bis- and tris-aromatic triols (CD4420), podocarpic acid derivative (VDRL-1), and steroidal compounds such as the secondary bile acid lithocholic acid and its derivatives. The structure and chemistry of these molecules are described in the chapter.

Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone, and notably, this molecule lowers LDL (-74%) and raises HDL (+73%) in a hamster model of dyslipidemia. This is the first reported crystal structure of the GR LBD bound to a nonsteroidal antagonist, and this article provides additional elements for the design and pharmacology of clinically relevant nonsteroidal GR antagonists that may have greater selectivity and fewer side effects than their steroidal counterparts.