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A structure-activity study of the dual acting ACE/NEP inhibitors related to 1a and 1b was undertaken to determine the parameters critical for activity versus ACE and NEP in vitro.

A series of bicyclic and monocyclic diazepinones were incorporated as conformationally restricted dipeptide surrogates in mercaptoacetyl dipeptide dual-acting ACE/NEP inhibitors. A comparison was made between these two classes of compounds as well as with the previously disclosed ACE/NEP inhibitor 1. Compound 2a was found to exhibit high potency versus both enzymes in vitro as well as in vivo.

A structure-activity study of dual-acting ACE/NEP inhibitor 1A was initiated in order to ascertain what parameters effect in vitro activity versus ACE and NEP. Unlike NEP, ACE was found to be remarkably tolerant to a wide variety of permutations with respect to both the lactam nucleus and the pharmacophore side chain.

Mercaptoacyl dipeptides were prepared as dual-acting ACE/NEP inhibitors. Inhibition of each enzyme may be explained by different binding models. Structure-activity studies determined that, in this series of compounds, the mercaptopropanoyl dipeptide framework leads to increased affinity for NEP but diminished ACE activity in vivo .

A series of benzo-fused lactams were incorporated as conformationally restricted dipeptide mimetics of Ala-Pro in dual-acting ACE/NEP inhibitors 1 and 2. The result of this modification led to compounds possessing excellent inhibitory potency versus ACE and NEP both in vitro and in vivo.