Citation

Vergely I, Boggetto N, Okochi V, Golpayegani S, Reboud-Ravaux M, Kobaiter R, Joyeau R, Wakselman M. Eur. J. Med. Chem. 1995; 30(3): 199-208.

Copyright

(Copyright © 1995, Elsevier Publishing)

DOI

10.1016/0223-5234(96)88226-2

PMID

unavailable

Abstract

A series of functionalized N-aryl azetidin-2-ones with a latent alkylating group was prepared by a flexible four-step synthesis. They met criteria expected for a suicide-type inactivation of human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE), with no inactivation of trypsin- and chymotrypsin-like proteases. The inhibition potency was dependent on the halogen substituents at C-3 (F, F; Cl, Cl; Br, Br) and the nature and the position relative to nitrogen of the latent benzylic leaving group (F, Cl, Br). Better inactivations of HLE compared with PPE were observed with azetidinones gem-disubstituted by Cl and Br rather than by F. Their protio analogs, which are devoid of the latent quinoniminium methide electrophile, behave as simple substrates of elastases. © 1995 Elsevier, Paris.

Language: en

Keywords

human; article; controlled study; nonhuman; enzyme inhibition; drug synthesis; suicide substrate; leukocyte; structure activity relation; pancreas; TMS; leukocyte elastase; -lactam; 2 azetidinone derivative; Bz-Arg-p-NA tN-benzoylarginine-p-nitroanilide; dimethylformamide; dimethylsulfoxide; DMF; DMSO; elastase; HLE (EC 3.4.21.37); human leukocyte elastase; inhibitor; MeO-Suc-Ala2-Pro-Val-p-NA methoxysuccinylalanylalanylprolylvaline-p-nitroanilide; N-bromosuccinimide; NBS; pancreatic elastase; porcine pancreatic elastase; PPE (EC 3.4.21.36); quinoniminium methide; Suc-Ala2-Pro-Phe-p-NA succinylalanylalanylprolylphenylalanine-p-nitroanilide; Suc-Ala3-p-NA succinylalanylalanylalanine-p-nitroanilide; tetramethylsilane; β