Replacement of key structural or binding elements of a peptide lead with nonpeptide components can improve affinity and metabolic stability (1 –5 ). Such a strategy was successfully applied to the generation of potent, cell-permeable inhibitors of Ras famesyltransferase (FTase) (6 ,7 ). The central pair of amino acids in the CAAX tetrapeptide was replaced with the nonpeptide scaffold 3-methylamino-1-carboxymethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one, (N-Me)BZA, shown below.
