Design, synthesis and pharmacological evaluation of 3-benzylazetidine-2-one-based human chymase inhibitors

2-Azetidinone – A new profile of various pharmacological activities

“…Aoyama et al have designed a novel series of 3-Benzylazetidine-2-one derivatives and evaluated for their activity as chymase inhibitors [64]. The results of the inhibitory activity of the designed compounds showed that compound (3S,4S)-3-Benzyl-4-(4-methylpiperazincarbonyl) phenoxy-1-[(R)-1-(phenylethyl)aminocarbonyl] azetidin-2-one possessed high potency against human chymase (IC 50 0.46 nM), but unstable in human plasma The SAR study suggested that 3b-isomers are more potent than 3a-isomers.…”

Therapeutic potential of non-peptide chymase inhibitors

“…In 2001, chemists from Shionigo Research Laboratories described the design and synthesis of human chymase inhibitors based on 3-benylazetidine-2-one [50] . Compound 23,…”

“…azetidin-2-one, was shown to inhibit human chymase with an IC 50 of 3.1 nM and be stable in human plasma with an half-life of 6 h [50] . Further modification of Compound 23 led to BCEAB, 4-[1-{[ bis -(4-methylphenyl)-methyl-carbamoyl}-3-(2-ethoxybenzyl)-4-oxo-azetidine-2-yloxy]benzoic acid ( Figure 3 ), which has been evaluated in animal models of disease.…”

3D QSAR Pharmacophore Modeling, in Silico Screening, and Density Functional Theory (DFT) Approaches for Identification of Human Chymase Inhibitors

“…Several chymase inhibitors such as sulfonyl fluoride derivatives [10], Boc-Val-Pro-Phe-CO 2 Me [11], Z-Ile-Glu-Pro-Phe-CO 2 Me, (F)-Phe-COGlu-Asp-ArgOMe [12], N -(2-Naphthyl) carboxamido derivatives [13], N -(2,2-dimethyl-3-( N -(4-cyanobenzoyl)amino) nonanoyl)- l -phenylalanine ethyl ester [14], 3-benzylazetidine-2-one derivatives [15], 1,3-diazetidine-2,4-dione derivatives [16], methyllinderone derivatives [17], chloromethyl ketone derivatives [18], 1-oxacephem derivatives [19], and 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives [20] have been reported previously. In general, chymase inhibitors readily decompose in plasma, thus the stability of the chymase inhibitors in human plasma has always been a matter of great concern.…”