Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors

Abstract

Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.

Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

“…[19] As shown in Figure 3, the LC 50 values of ezetimibe were 87.7 μM against HEK293T and 85.6 μM against L02, respectively. Here, the cytotoxicity of the above compounds was determined by the MTT cell proliferation assay in normal human cell lines, L-02 (human normal liver cells) and HEK293T (human embryonic kidney cells).…”

“…In general, the LC 50 values higher than 100 μM were considered non-toxic. [19] As shown in Figure 3, the LC 50 values of ezetimibe were 87.7 μM against HEK293T and 85.6 μM against L02, respectively. Fortunately, the LC 50 values of compound 14q were higher than 200 μM in both cell lines, and 14q displayed far lower cytotoxicity than ezetimibe.…”

Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors

“…For that reason, either phenyl or benzyl substituent was attached to the amide group. In continuation of our research, 14–19 we synthesized six new ezetimibe analogs 5a – f ( Fig. 2 ) from trans -3-amino-(3 R ,4 R )-β-lactam 2 and determined their cytotoxicity, as well as in vitro and in vivo activity.…”

Synthesis, Separation and Absolute Configuration Determination by ECD Spectroscopy and TDDFT Calculations of 3‐Amino‐β‐lactams and Derived Guanidines

“…[6] We have, on the other hand, recently developed new ezetimibe analogues from 3amino--lactam by introducing side-chain functional groups applying N-alkylation [8] or N-acylation reactions (Scheme 1). [6] We have, on the other hand, recently developed new ezetimibe analogues from 3amino--lactam by introducing side-chain functional groups applying N-alkylation [8] or N-acylation reactions (Scheme 1).…”

“…The use of (-)-menthyl glycine ester results in the exclusive formation of (3R,4R)-transamino--lactam, [8,13] whereas the (+)-menthyl ester gives the enantiomerically pure (3S,4S)-trans enantiomer. The same route afforded analogues with a 1,3-benzodioxole instead of the p-methoxyphenyl group.…”