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

Abstract

The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counter-receptors 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. Pharmaceutical 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 the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in 1 with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of 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 expression. This position is presumably close to the solvent-accessible region of the target protein-inhibitor complex. An attempt to install a water-solubilizing group at the para-position of the phenoxy group to increase the aqueous solubility of this lead series through various linkages failed to provide an ideal inhibitor. Only small substituents such as fluorine are tolerated at the meta- and ortho-positions of the 4-phenoxy to retain a good in vitro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are among the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC(50) < 5 nM for ICAM-1) and selective (>200-fold vs VCAM-1) inhibitors with a good pharmacokinetic profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.

Global Gene Analysis of <i>Erigeron canadensis-</i>Treated TNF-α-, IL-4- and IL-1β-Stimulated A549 Human Epithelial Cells

“…␤ 1 and ␤ 2 integrins) results in the capture, rolling and firm adhesion of the leukocytes to the vascular endothelium. The arrested leukocytes then migrate across the vascular wall and move toward the lesion along the chemotactic gradient [2,9,15,16] . In this study, we detected a downregulation of SELE , VCAM1 , ICAM1 , ITGA7 and ITGB2 in EC-treated A549 cells ( table 1 , fig.…”

Host ICAMs play a role in cell invasion by Mycobacterium tuberculosis and Plasmodium falciparum

“…The reported IC 50 of A205804 for selective inhibition of ICAM-1 is 25 nM 37 . THP-1 macrophages treated with suboptimal (20 nM) and optimal (50 nM) of A205804 were analysed for H37Rv-GFP infection and ICAM-1 expression.…”

A Facile Synthesis and Discovery of Highly Functionalized Tetrahydro-pyridines and Pyridines as Antimycobacterial Agents

“…Tetrahydropyridine derivatives are useful against several metabolic disorders and human ailments and are involved in monoamine oxidase based mechanism in Parkinson's disease 18,19) and as inhibitors of farnesyl transferase 20) and dihydroorate dehydrogenase 21) and also play key roles in many disease processes. The pyridine motif is found in various therapeutic agents, including numerous antihistamines, 22) antiseptic, 23) antiarrythmic, 24) antirheumatic, 25) and other pharmaceutical agents and natural products. They also play a pivotal role in catalyzing both biological and chemical reactions.…”