生物活性

• 描述Dipeptidylpeptidase 4 (DPP4) belongs to the S9b gene family of postproline serine peptidases. It acts mostly as a secreted membrane protein, mediating the degradation and inactivation of glucagon-like peptide (GLP)-1 and gastric inhibitory protein (GIP)^[3]. Trelagliptin succinate, a novel DPP4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients and it exhibits >10,000-fold selectivity over related proteases including DPP8 and DPP9. Trelagliptin exhibited potent inhibitory activity toward DPP4 prepared from Caco-2 cells with an IC₅₀ value of 5.4 nM. It also inhibited human, dog, and rat plasma DPP4 activity with IC₅₀ values of 4.2, 6.2, and 9.7 nM respectively. In a phase 2 dose-ranging study using a sigmoid Emax model, the plasma trelagliptin concentration estimated to yield 50% and 70% inhibition of plasma DPP4 activity was 1.43 ng/mL and 2.31 ng/mL, respectively^[4].
• 作用机制The aminopiperidine forms a salt bridge to Glu205/Glu206, while the cyanobenzyl group effectively fills the S1 pocket and interacts with Arg125.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01632007	Diabetes Mellitus	Phase 3	Completed	-	Japan ... more >> Akita-shi, Akita, Japan Matsudo-shi, Chiba, Japan Fukuoka-shi, Fukuoka, Japan Fukuyama-shi, Hiroshima, Japan Ishikari-shi, Hokkaido, Japan Nakagawa-gun, Hokkaido, Japan Sapporo-shi, Hokkaido, Japan Naka-shi, Ibaragi, Japan Sagamihara-shi, Kanagawa, Japan Kumamoto-shi, Kumamoto, Japan Kashiwara-shi, Osaka, Japan Osaka-shi, Osaka, Japan Suita-shi, Osaka, Japan Arakawa-ku, Tokyo, Japan Bunkyo-ku, Tokyo, Japan Chiyoda-ku, Tokyo, Japan Chuo-ku, Tokyo, Japan Itabashi-ku, Tokyo, Japan Katsushika-ku, Tokyo, Japan Mitaka-shi, Tokyo, Japan Shinjuku-ku, Tokyo, Japan Shunan-shi, Yamaguchi, Japan Collapse <<
  NCT02528019	Effects of the DPP-4 Inhibitor... more >>s or SGLT2 Inhibitors on the Protective Actions for Diabetic Complications Collapse <<	Phase 4	Unknown	August 2018	Japan ... more >> Kurume University Hospital Recruiting Kurume city, Japan, 830-0011 Contact: Nobuhiro Tahara, MD, PhD    +81-942-31-7580    ntahara@med.kurume-u.ac.jp    Contact: Sho-ichi Yamagishi, MD, PhD    +81-942-31-7562       Principal Investigator: Nobuhiro Tahara, MD, PhD Collapse <<
  NCT03231709	Type 2 Diabetes Mellitus	Phase 4	Completed	-	Japan ... more >> OCROM Clinic Suita, Osaka, Japan ToCROM Clinic Shinjuku, Tokyo, Japan Collapse <<

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• 参考文献

• [1] Zhang H, Sun L, et al. Identification, characterization and HPLC quantification of process-related impurities in Trelagliptin succinate bulk drug: Six identified as new compounds. J Pharm Biomed Anal. 2016 Sep 5;128:18-27.

  [2] Kaku K. First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother. 2015;16(16):2539-47.

  [3] Huan Y, Jiang Q, Liu JL, Shen ZF. Establishment of a dipeptidyl peptidases (DPP) 8/9 expressing cell model for evaluating the selectivity of DPP4 inhibitors. J Pharmacol Toxicol Methods. 2015 Jan-Feb;71:8-12. doi: 10.1016/j.vascn.2014.11.002. Epub 2014 Nov 15. PMID: 25464020.

  [4] Grimshaw CE, Jennings A, Kamran R, Ueno H, Nishigaki N, Kosaka T, Tani A, Sano H, Kinugawa Y, Koumura E, Shi L, Takeuchi K. Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism. PLoS One. 2016 Jun 21;11(6):e0157509. doi: 10.1371/journal.pone.0157509. PMID: 27328054; PMCID: PMC4915685.