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Title: Design Synthesis and Pharmacological evaluation of novel Cathepsin S inhibitors
Keywords: Synthesis and Pharmacological,evaluation of novel,Cathepsin S inhibitors
University: Birla Institute of Technology and Science
Completed Date: 1/8/2014
Abstract: Neuropathic pain is a complex clinical syndrome, which may be intractable in several distinct common neurological disorders such as diabetic neuropathy, herpes zoster, trigeminal neuralgia, radiculopathies, cancer, spinal cord injury, multiple sclerosis and stroke. Several extensive research reports revealed that, Cathepsin S has crucial role in inflammatory neuropathic pain, where, extracellular Cathepsin S released from microglial cells due to p38 mitogen-activated protein kinase pathway, liberates soluble fractalkine from DRG neurons, which further induces the release of inflammatory mediators that activate neurons, which signals pain to the higher centers leading to neuropathic pain. newlineIn the present study, a diverse set of molecules as CatS inhibitors were initially identified using lead identification strategies of ligand based and structure based drug design methods. Lead molecules obtained from the lead identification strategies, were further experimentally evaluated with in vitro enzymatic assays, where, the most active lead compound was found to be Lead 9 with IC50 of 3.09 and#956;M, but later failed in glioblastoma growth inhibition studies. Further, second most active compound Lead 8 showed good enzyme inhibition (6.58 and#956;M) and with GIC50 of 0.477 and#956;M and with gt100 fold selectivity index as well as with low cytotoxicity on normal cells. Thus, Lead 8 was selected as final lead molecule to proceed for synthesis and biological evaluation as a step for lead optimization. newlineAll the synthesized molecules from the Lead 8 (1,2,4-triazol thiol arylacetamide moiety) were interpreted with the SAR studies with help of binding interaction patterns and atom based QSAR predictions in relation with enzymatic and biological evaluations. However, all the compounds were forwarded to the preliminary neuropathic pain in vivo animal screening. In the preliminary behavioral assessments on CCI animal models, 18 compounds along with parent compound Lead 8 were further analyzed to understand the ED50 values. Among all the compounds.
Pagination: 8.02 MB
Appears in Departments:Pharmacy

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