The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

The design, synthesis, and biochemical profile of meta-substituted benzofused macrocyclic lactams are described. The meta-substituted benzofused macrocyclic lactams were designed to have a degree of flexibility allowing the amide bond to occupy two completely different conformations while maintaining sufficient rigidity to allow for strong interaction between enzyme and inhibitor. Using TFIT, a novel molecular superimposition program, it was shown that the meta analogs could be readily superimposed onto our ACE inhibitor template whereas no low-energy superimpositions of the ortho-substituted macrocycles could be found. The macrocycles were prepared by tethering aldehyde 1 derived from S-glutamic acid or S-aspartic acid to a meta-substituted phosphonium bromide 2. Homologation to a monocarboxylic acid methyl ester malonate followed by deprotection and cyclization gave the macrocyclic frame. Further manipulation gave the desired compounds. Unlike the ortho-substituted benzofused macrocyclic lactams described in the previous paper which are selective NEP inhibitors, the meta-substituted compounds are dual inhibitors of both NEP and ACE. The most potent member of this new series, compound 16a, inhibited both enzymes with an IC50 = 8 nM in NEP and 4 nM in ACE.

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