Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB.
J Med Chem
; 67(9): 7504-7515, 2024 May 09.
Article
em En
| MEDLINE
| ID: mdl-38640354
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
4-Butirolactona
/
Antialérgicos
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article