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.

P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.

With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.

Novel P4 truncated tripeptidyl alpha-ketoamides as HCV protease inhibitors.

We describe herein the synthesis and evaluation of two series of P-4 truncated tripeptidyl alpha-ketoamides as HCV serine protease inhibitors. The most promising compound disclosed in this communication 7b demonstrated enzyme binding affinity (K(i)) at 0.27 uM.

Synthesis and evaluation of tripeptidyl alpha-ketoamides as human rhinovirus 3C protease inhibitors.

We describe herein the synthesis and biological evaluation of a series of tripeptidyl alpha-ketoamides as human rhinovirus (HRV) 3C protease inhibitors. The most potent inhibitor discussed in this manuscript, 4I, exhibited impressive enzyme inhibitory activity as well as antiviral activity against HRV-14.

Glycopeptide carboxamides active against vancomycin-resistant enterococci.

Glycopeptide antibiotics were synthesized via the PyBOP mediated condensation of aliphatic, heterocyclic and aromatic amines with the C-terminus of vancomycin, LY264826 (A82846B) and semi-synthetic derivatives of these natural products. Amides of LY264826 and vancomycin demonstrated excellent activity against staphylococci and streptococci as compared to the parent natural product. However, the amides of N-alkylated LY264826 and N-alkylated vancomycin were active against vancomycin-resistant enterococci as well as other gram-positive pathogens such as Staphylococcus aureus, S. haemolyticus, S. epidermidis and Streptococcus pneumoniae.