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

  • J Med Chem. 2024 May 9;67(9):7504-7515. doi: 10.1021/acs.jmedchem.4c00354.
Chun-Lan Xie  1  2 ,  Hong-Xiu Xiao  2  3 ,  Pei-Fang Song  4 ,  Qing-Mei Liu  5 ,  Haoxiang Wei  3 ,  Liang Wu  4 ,  Guang-Hao Zhu  4 ,  Guang-Ming Liu  5 ,  Yandong Zhang  3 ,  Ping Wang  4 ,  Xian-Wen Yang  1  2
Affiliations
  • 1. School of Pharmacy, Hainan Medical University, Hainan Academy of Medical Sciences, No. 3 Xueyuan Road, Haikou 571199, China.
  • 2. Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, Fujian 361005, China.
  • 3. State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, iCHEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
  • 4. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 5. College of Ocean Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, China.
PMID: 38640354 DOI: 10.1021/acs.jmedchem.4c00354
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.

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