Nitric oxide (NO) is a small reactive molecule with an important role in various physiological processes, including modulation of inflammatory responses and regulation of vascular tone.  Nitric oxide synthase (NOS) catalyzes the formation of NO and L-citrulline from L-arginine (Arg) and oxygen.  The NOS family consists of three known mammalian isoforms.  Neuronal NOS (nNOS) and endothelial NOS (eNOS) are constitutively expressed under noninflammatory conditions, and their activity is tightly regulated by Ca²⁺ calmodulin. Inducible NOS (iNOS) is a key mediator of inflammation and host defense systems.  Expression of iNOS is induced at a transcriptional level by inflammatory stimuli, including interferon (IFN), interleukin (IL)-1, tumor necrosis factor (TNF), and bacterial lipopolysaccharide (LPS).  Production of excess NO and prolonged induction of iNOS have been observed in various inflammatory and autoimmune diseases, including septic shock, hemorrhagic shock, systemic lupus erythematosus, Sjögren's syndrome, vasculitis, rheumatoid arthritis (RA) and osteoarthritis (OA).  Selective inhibitors of iNOS would therefore be a useful approach to the treatment of inflammatory diseases and pain. As a part of our discovery research program in this area, a series of novel imidazolepyrimidines was designed and synthesized as potent inhibitors of iNOS dimer formation, a key prerequisite for proper functioning of the enzyme. The details of the synthesis and the biological activity of these novel iNOS dimerization inhibitors will be presented.