orders of magnitude. these results also indicate that the n-domain possess a broader selectivity than the c-domain. another difference between the older ace inhibitors and rxp 407 is the molecular size of the compound. the older ace inhibitors had mostly been interacting with s1’, s2’ and s1 subsites but rxp 407 interacts in addition with the s2 subsite. this also is important for the selectivity of the inhibitor since the aspartic side chain and n-acetyl group are located in the p2 position. drug design of rxpa 380 rxpa380 was the first inhibitor that was highly selective of the c-domain of ace, it has the formula phe-phe-pro-trp. the development of this compound was built on researches that showed that some bradykinin-potentiating peptides showed selectivity for the c-domain and all had several prolines in their structure. these observations lead the researchers to synthesize phosphinic peptides containing a proline residue in the p1’ position and evaluating these compounds led to the discovery of rxpa380. to study the roles of the residues on rxpa380 the researchers made 7 analogues of rxpa380. all of the compounds made were obtained as a mixture of either 2 or 4 diastereoisomers but all of them were easily resolved and only one of them was potent. this is consistent with the initial modeling studies of rxpa380 which showed that only one diastereomer could accommodate in the active site of germinal ace. analogues where pseudo-proline or tryptophan residues had been substituted showed less selectivity than rxpa380. this is probably because these two analogues have more potency toward the n-domain than rxpa380 does. substituting both of these residues gives great potency but none selectivity. this shows that pseudo-proline and tryptophan residues accommodate well in the c-domain but not in the n-domain. 2 more analogues with both pseudo-proline and tryptophan but missing the pseudo-phenylalanine residue in p1 position showed low potency for n-domain, similar to rxpa380. this supports the significant role of these two residues in the selectivity for c-domain. these two analogues also have less potency for the c-domain which shows that the c-domain prefers pseudo-phenylalanine group in p1 position. modeling of rxpa380-ace complex showed that the pseudo-proline residue of the inhibitor was surrounded by amino acids similar to that of the n-domain thus interactions with s2’ domain might not be responsible for the selectivity of rxpa380. 7 of 12 amino acids surrounding tryptophan are the same in c- and n-domain, the biggest difference is that 2 bulky and hydrophobic amino acids in the c-domain have been replaced with 2 smaller and polar amino acids in the n-domain. this indicates that low potency of rxpa380 for n-domain is not because the s2’ cavity does not accommodate the tryptophan side chain but rather that important interactions are missing between the tryptophan side chain and the amino acids of the c-domain. based on the proximity between the tryptophan side chain and asp1029 there is also a possible hydrogen bond between the carboxylate of asp1029 and the nh indole ring in the c-domain but this interaction is much weaker in the n-domain.