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Urea - Inosine monophosphate dehydrogenese (IMPDH), a key enzyme that is involved in the de novo synthesis of purine nucleotides, is an attractive target for immunosuppressive, anticancer, and antiviral therapies (18). Compound 15 (VX-497) is an orally active inhibitor of IMPDH (19) recently discovered using a structure-based design approach. Using a bioisosteric replacement of the amide portion of the urea moiety with an oxazole, a novel series of potent inhibitors such as 16 with low nanomolar potency against the enzyme were developed. Compound 16 also showed excellent In vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats (20). Replacing the urea linkage in 15 with an oxalamic diamide linkage also led to a series of potent IMPDH inhibitors as exemplified by 17 (21).

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