Reno-selective nitric oxide donor drugs: preliminary toxicology and metabolism studies. (360G-Wellcome-063729_Z_01_A)

The proposed research is in support of an existing Wellcome Trust Development Award to develop novel renoselective nitric oxide donor drugs fir use in acute renal failure. The Development Award is progressing to schedule and we now ha ve prototype pro-drugs with pharmacological characteristics to suggest that th ey will be renoselective. During recent discussions, Wellcome Trust suggested that we consider conducting a preliminary screen to determine the toxicology a nd metabolism of candidate compounds at an early stage in order to optimise le ad selection for future development. Studies of this type will be outsourced t o a specialised company (CXR Biosciences, Dundee). Studies have been designed to assist lead selection and optimisation based on the potential for adverse m etabolic or safety characteristics of the active metabolite as well as its gen eration from the prodrug in kidney and other tissues. CXR Biosciences have con siderable experience in this area and will use a combination of experiments in human and rat microsomes, hepatocytes and tissue homogenates to establish these key criteria in our compounds for further development, and in optimising th e drug like characteristics of compounds to improve the chances of clinical success.