2. Academic Validation
  3. The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119

The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119

  • Eur J Med Chem. 2020 Feb 15;188:112017. doi: 10.1016/j.ejmech.2019.112017.
Gang Li 1,  Bingxu Meng 1,  Baokun Yuan 1,  Yi Huan 1,  Tian Zhou 1,  Qian Jiang 1,  Lei Lei 1,  Li Sheng 1,  Weiping Wang 1,  Ningbo Gong 1,  Yang Lu 1,  Chen Ma 1,  Yan Li 1,  Zhufang Shen 2,  Haihong Huang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: shenzhf@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address: joyce@imm.ac.cn.
PMID: 31926470 DOI: 10.1016/j.ejmech.2019.112017
Abstract

A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.

Keywords

DPP-IV; Druggability; GPR119; HBK001; Xanthine compounds.

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