Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.     

Discovery of novel non-peptide CCR1 receptor antagonists

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.