title: Synthesis, Biological Evaluation, and Molecular Docking of (R)-2-((8-(3-aminopiperidin-1-yl)-3-methyl-7-(3-methylbut-2-en-1-yl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)benzonitrile as Dipeptidyl Peptidase IV Inhibitors.
abstract: Type 2 diabetes (T2D) is classified as a major metabolic disorder, which has affected approximately 194 million people worldwide. DPP-IV inhibitors as a new therapy have shown several advantages over traditional antidiabetic drugs. Based on the similar binding modes of Alogliptin and Linagliptin, molecular operation was conducted via combining pharmacophore hybridization with structural optimization between the two market drugs and racemic compounds 40 and 43 were reported as DPP-IV inhibitors in our previous studies. But the majority of DPP-IV inhibitors have developed into a small molecule with certain conformation; in this study, we described the synthesis, biological evaluation, and molecular docking of corresponding enantiomers of compounds 40 and 43. The most potent inhibitor is (R)-40 (IC50  = 23.5 nm, F = 74.67%, T1/2  = 4 h), which exhibited moderate antihyperglycemic activity as compared to the standard antidiabetic drug Linagliptin in OGTT. In addition, compound (R)-40 effectively improved the pathological state of DIO mice. Molecular docking studies clarified the favorable binding affinity between compound (R)-40 and DPP-IV active site. Thus, compound (R)-40 would be entitled to further development as a drug candidate on the basis of the suitable pharmacokinetic (PK) and desirable pharmacodynamic (PD) profiles.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ran
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China.
authors.forename: Heying
authors.initials: H
authors.lastname: Pei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan Road 4, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D020134:Catalytic Domain; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy / Q000209:etiology; D012372:ROC Curve; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; C014356:benzonitrile; D018819:Dipeptidyl Peptidase 4
keywords: DPP-IV inhibitor; enantiomer; glucose homeostasis; pharmacophore hybridization