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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Li G,Meng B,Yuan B,Huan Y,Zhou T,Jiang Q,Lei L,Sheng L,Wang W,Gong N,Lu Y,Ma C,Li Y,Shen Z,Huang Hdoi
10.1016/j.ejmech.2019.112017subject
Has Abstractpub_date
2020-02-15 00:00:00pages
112017eissn
0223-5234issn
1768-3254pii
S0223-5234(19)31175-4journal_volume
188pub_type
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