Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)thieno[2,3-c]pyridines with fine-tuning at C-2 carbamides

The elevated expression of cell adhesion molecules (CAMs) on the lumenal su rface of vascular endothelial cells is a critical early event in the comple x inflammatory process. The adhesive interactions of these CAMs that includ e E-selectin, ICAM-1, and VCAM-1 with their counterreceptors on leukocytes, such as integrins of the alpha (L)beta (2) family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmac eutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at t he C-4 and C-2 positions to identify a more potent drug candidate with a go od pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in I with an oxygen atom eliminated one of the two major met abolites for this lead molecule. The para-position of the 4-phenoxy group o f the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expre ssion. This position is presumably close to the solvent-accessible region o f the target protein-inhibitor complex. An attempt to install a water-solub ilizing group at the para-position of the phenoxy group to increase the aqu eous solubility of this lead series through various linkages failed to prov ide an ideal inhibitor. Only small substituents such as fluorine are tolera ted at the meta- and ortho-positions of the 4-phenoxy to retain a good in v itro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are a mong the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC50 < 5 nM for ICAM-1) and selective (> 200-fold vs VCAM-1) inhibitors with a good pharmacokineti c profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.