Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB

Food
allergy (FA) poses a growing global food safety concern, yet
no effective cure exists in clinics. Previously, we discovered a potent
antifood allergy compound, butyrolactone I (BTL-I, 1),
from the deep sea. Unfortunately, it has a very low exposure and poor
pharmacokinetic (PK) profile in rats. Therefore, a series of structural
optimizations toward the metabolic pathways of BTL-I were conducted
to provide 18 derives (2–19). Among
them, BTL-MK (19) showed superior antiallergic activity
and favorable pharmacokinetics compared to BTL-I, being twice as potent
with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration–time
curve (AUC0–∞) were 565 and 204 times higher
than those of BTL-I, respectively. These findings suggest that butyrolactone
methyl ketone (BTL-BK) could serve as a drug candidate for the treatment
of FAs and offer valuable insights into optimizing the druggability
of lead compounds.