Angiotensin-I converting enzyme (ACE) has been successfully targeted in the treatment of hypertension and cardiovascular disease for over 30 years. Subsequent research into the structure and function of the enzyme has shown ACE to be a dual-domain metalloprotease with a wider array of substrates than previously known. The two distinct catalytic domains (termed the N and C domains) vary greatly in their substrate specificity (1). Genetic knock-out experiments have highlighted the benefits of C-domain selective ACE inhibition in treating hypertension and N-domain-selective ACE inhibition in the treatment of pulmonary and cardiac fibrosis (2,3). With high resolution crystal structures of both domains interacting with a variety of ligands, it is now possible to examine the binding site differences and exploit them in the design of N-domain selective inhibitors (4). Mutating the C domain E403 to R381, its Ndomain counterpart in the P2 subsite revealed that this residue is crucial for N-domain selective binding (5). A variety of Computer Aided Drug Design (CADD) techniques have been employed to target this interaction and design N-selective ACE inhibitors with favourable R381 interactions. A de novo combinatorial approach has been adopted and a virtual library of compounds has been assembled from an SAR series based on S2 modifications to enalaprilat, a non-domain selective ACE inhibitor. This library has been subjected to a constrained docking simulation accompanied by Molecular Mechanics – Generalised Born Surface Area (MM-GBSA) free energy binding calculations using the Glide and Prime applications from the Schrodinger Small Molecule Drug Discovery (SMDD) software suite (6,7). The most promising hit has been synthesised using methyl ester acid protected acids and a combination of peptide coupling and nucleophilic substitution reactions. It’s inhibition on both ACE domains has been evaluated using a fluorogenic assay (8).