"The consortium has a lead series of p38 inhibitors with unusual anti-inflammatory properties. The drug leads were originally elaborated as a potential therapy for inflammatory bowel disease, however, the potency of the compounds and their general anti-inflammatory mode of action has raised the possibility of studying their utility in other diseases including rheumatoid arthritis. In addition, feedback from licensing partners has indicated that clear activity in a range of other disease models would dramatically increase interest. A key issue in bringing substances of this class to the clinic is variable patient response to p38 inhibitors in previous trials. Data to date have indicated that there is a potential groups of responders for whom therapy with this class is highly beneficial. The effect of non-responders has, however, made trial outcomes to variable to warrant further development. To solve this problem, we intend to further extend proof-of-concept in patient stratification to allow us to select responder populations for initial patient trials. The objectives of the project are, therefore: § To prepare analogs of the existing compounds § Conduct pre-clinical models for rheumatoid arthritis, IBD, sepsis, liver fibrosis and motilin dependent gut stimulation § Examine the activity of the compounds in human tissue explant models § Select a pre-clinical candidate class § Develop a scaled-up process for GMP synthesis of the lead § Conduct a survey of p38 expression in IBD and RA sub-types at various stages of disease and correlate this plasma markers. § Based on results of tissue explant studies and p38 expression, select a patient stratification protocol for phase 2A studies in man."