High neutral endopeptidase

The synthesis of the CG525155 (a neutral endopeptidase inhibitor) required a Pd catalyzed Tsuji-Trost reaction as the key step following the strategy described by Johnson. Starting from the optically active allenyl amino acid methylester 91 (synthesized in several steps from 90), the seco-derivative 92 as the crucial precursor was generated in several steps in high yield. The Pd (0)... 

Mixanpril, N-[(2S,3 R)-2-benzoylthiometh-yl-3-phenylbutanoyl]-L-alanine, a dual inhibitor for the neutral endopeptidase-24.11 (NEP) and the angiotensin-converting enzyme (ACE). The orally administerable mixanpril is important for the treatment of high blood pressure and cardiac defects [S. Turcaud et al., Bioorg. Med. Chem. Lett. 1995, 5, 1893]. 

We observed no undesired activities on the human hERG channel and no hints for genotoxicity in the micronucleus and for mutagenicity in the AMES II test system. In addition, this compound had low log D and PSA values and a high solubility. This compound had a limited cell permeability as measured in the Caco-2 assay. Regarding selectivity, 9b showed a submicromolar activity on neutral endopeptidase (NEP), which is another major peptidase involved in bradyki-nin metabolism [25,39]. 

Cohen AJ, King TE, Gilman LB, et al. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998 158 1593-1599. 

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