Design, Synthesis, and Biological Evaluation of a Novel Series of 4‑Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

To discover a novel
series of potent inhibitors of enteropeptidase,
a membrane-bound serine protease localized to the duodenal brush border,
4-guanidinobenzoate derivatives were evaluated with minimal systemic
exposure. The 1c docking model enabled the installation
of an additional carboxylic acid moiety to obtain an extra interaction
with enteropeptidase, yielding 2a. The oral administration
of 2a significantly elevated the fecal protein output,
a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas
subcutaneous administration did not change this parameter. Thus, systemic
exposure of 2a was not required for its pharmacological
effects. Further optimization focusing on the in vitro IC50 value and T1/2, an indicator of dissociation
time, followed by enhanced in vivo pharmacological activity based
on the ester stability of the compounds, revealed two series of potent
enteropeptidase inhibitors, a dihydrobenzofuran analogue ((S)-5b, SCO-792) and phenylisoxazoline (6b), which exhibited potent anti-obesity effects despite their low
systemic exposure following their oral administration to DIO rats.