Design Synthesis and Evaluation of Novel Anti rheumatic Agents

Abstract

Rheumatoid Arthritis (RA) an autoimmune disease leading to bone and joint damage. newlineWith availability of small molecules only for symptomatic treatment of RA, research and newlinedevelopment of small molecular inhibitor against promising targets of RA has attracted newlinethe attention of scientist s world-over. Of many targets identified for RA, TNF-and#945; newlineConverting Enzyme (TACE) enhances secretion of TNF-and#945; by cleaving pro-TNF-and#945; and newlinePeptidyl Arginine Deiminase 4 (PAD4) is involved in production of auto-antigens of RA. newlineTNF-and#945; is a key cytokine in RA. The disease severity is well correlated with TNF-and#945; level newlinein RA patients. With the success of anti-TNF-and#945; antibodies in RA treatment, development of newlineTACE inhibitors is a promising strategy to treat RA. From the available crystal structure of newlineTACE (2OI0), virtual database of 70 TACE inhibitors of benzophenone and urea series was newlinedesigned using structure based drug design approach. Promising designed molecules were newlinesynthesized and enzyme inhibition assay was carried out. Urea derivatives showed newlinerelatively higher activity compared to benzophenone derivatives in in vitro assay. In vitroin newlinesilico correlation showed that solubility is an important factor in determining in vitro newlineactivity. newlineWith the understanding of PAD4 mechanism of action and other arginine mimetic newlineinhibitors, attempt was made to design reversible arginine mimetic inhibitors. Using newlinecomputational tools and with knowledge base of 642 arginine mimetic compounds, a new newlinepharmacophore was proposed, based on which possible reversible PAD4 inhibitors newlinebelonging to benzamide and benzamidine series were designed. After in silico evaluation, newlineactive compounds were synthesized and screened for in vitro PAD4 inhibitory potential. In newlinep-(aminomethyl)-benzamide series many compounds showed moderate activity and N-[4- newline(aminomethyl)phenyl]-2-(2-methoxyphenyl)acetamide (M2MBN) was identified as most newlinepotent reversible PAD4 inhibitor. Reason for enhanced binding of M2MBN to PAD4 was newlinefurther studied by molecular simulation. 16 ns simulation showed .