Medicinal Chemistry Case History: Structure-Based Drug Design of Oral and Inhaled p38 MAP Kinase Inhibitors as Clinical Candidates

This article summarizes the identification and design optimization of (i) a novel series of Asp-Phe-Gly (DFG)-in binding inhibitors of p38 mitogen-activated protein kinase (MAPK) kinase as oral agents and (ii) a novel series of DFG-out binding inhibitors of p38 MAPK as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure-based drug design and “inhalation by design” principles have been applied to the optimization of the lead series, exemplified by the clinical agents PH-797804 and PF-3715455. Both agents have progressed into clinical development. An update on data obtained and their current status is also provided.