VIRTUAL SCREEENING AND PHARMACOLOGICAL EVALUATION OF NEWER BTK INHIBITIORS AS POTENT ANTI-RHEUMATOID ARTHRITIC AGENTS

Rheumatoid arthritis is a chronic autoimmune disease affecting 1% of the world wide population. Recent researches suggested that the need for discovery of new therapeutic disease modifying anti-rheumatoid arthritis drugs (DMARD’s). BTK (Bruton’s tyrosine kinase) is cytoplasmic, non receptor tyrosine kinase and it is efficient target for the treatment of rheumatoid arthritis. This encouraged us to design a novel series of potent BTK inhibitor. The BTK inhibitor containing five features of Pharma-cophore, One Hydrogen bond donor (HBD), one hydrogen bond acceptor lipid (HBAL) and three hydrophobic features (HYP). Five different ligands containing 4, 5-di-substituted imidazole as heterocyclic nucleus have been designed and optimized by using Molecular docking, Lipinski rule of five and toxicity prediction (ADMET). The optimized ligands were synthesized based on the synthetic feasibility and characterized by using different spectral studies such as IR, 1H NMR, 13C NMR and GC-MS. The synthesized compounds were evaluated for their in vitro Anti-arthritic activity using protein denaturation method and all were found to exhibit an effective inhibition against the protein. Out of the five synthesized compounds IPABA was found to be a most effective with percentage inhibition of protein denaturation at 1000μg/ml when compared with the other three synthesized compounds and it will take for further in-vivo anti-rheumatoid arthritis activity by using adjuvant induced arthritic model. The effect of synthesized compound IPABA decreased the bone erosion, spleen enlargement and rheumatoid factor at the dose of 100mg/kg and 200mg/kg compared to the disease control group but significantly less compared to standard drug dexamethasone 5mg/kg.