Design of the first highly potent and selective aminopeptidase N (EC 3.4.11.2) inhibitor (original) (raw)

A series of phosphinic compounds mimicking the transition state of substrates hydrolysed by aminopeptidase N (EC 3.4.11.2) were synthesized. These new compounds have potent inhibitory activities with Ki values in the nanomolar range. These derivatives behave as the most potent APN inhibitors designed to date. : Enzyme inhibitors / Phosphinic acids and derivatives / Resolution. APN, a monomeric or homodimeric type II membrane-bound zinc exopeptidase, is widely distributed in mammalian tissues including the central nervous system and is particularly abundant at the level of the kidney, the intestine and the lung ~. In vivo, this enzyme is involved in the metabolism of angiotensin III in the brain and peripheral organs 2, in the degradation of nociceptin 3 and in the inactivation of enkephalins, in association with neutral endopeptidase NEP 4. Furthermore, APN has been proved to be identical to a human lymphocyte surface cluster differentiation antigen CDI3 5, and to behave as a receptor for coronaviruses TGEV and 229E in pigs and humans 6.7. APN has been also reported to play an important role in the invasion of metastatic tumors in vitro 8.9. All these findings make this enzyme an interesting target for possible therapeutic applications, which require the development of potent and selective inhibitors.