Abstract
The family of p38 Mitogen-activated protein kinases, also known as MAPKs, area group of proteins that play a key role in signal cascades used for various cellular processes. Because p38 is involved with a large variety regulators and pathways, it is associated with many diseases. These include rheumatoid arthritis, Alzheimer’s disease, and COPD. Positive feedback loops of TNFα and NF-κB allow for excessive inflammatory responses. This causes uncontrolled regulation and leads to the damage of other cells or organs. This is present in various parts of the body such as in hands, digestive tract, and brain. Most of the diseases associated with inflammation caused by p38 over expression have no cure and methods such as therapy and common nonsteroidal anti-inflammatory drugs merely slow down the progression. In order to combat these diseases, a library of pyrazoles has been devised that have the potential to inhibit p38. These 1,5-diaryl pyrazoles may pave the way to controlling the diseases that are associated with p38. A computational molecular modeling and ligand docking approach was used to develop a new line of p38 inhibitors. Through very thorough screening methods involving analysis and optimization of ligand-protein interactions, ten compounds were chosen out of many thousands to be the lead compounds in the inhibitor design formulation. A synthetic scheme was devised by which these compounds could be synthesized. The feasibility of this reaction sequence was demonstrated by the successful synthesis of one of these potential inhibitors.