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File:Gemigliptin.svg
Clinical data
Other namesLC15-0444
Routes of
administration		Oral
ATC code
Pharmacokinetic data
Bioavailability94%(rat), 73%(dog), 26%(monkey)
Elimination half-life3.6 h(rat), 5.2 h(dog), 5.4 h(monkey)
Identifiers
  • 1-{(2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoropiperidin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC18H19F8N5O2
Molar mass489.36 g/mol g·mol−1
3D model (JSmol)
  • O=C1N(CC(F)(CC1)F)C[C@H](CC(N2CCc3c(C(F)(F)F)nc(C(F)(F)F)nc3C2)=O)N
  • InChI=1S/C18H19F8N5O2/c19-16(20)3-1-12(32)31(8-16)6-9(27)5-13(33)30-4-2- 10-11(7-30)28-15(18(24,25)26)29-14(10)17(21,22)23/h9H,1-8,27H2/t9-/m0/s1 checkY
  • Key:ZWPRRQZNBDYKLH-VIFPVBQESA-N checkY


Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and GIP incretin hormones which are inactivated by DPP-4. Gemigliptin was initially developed solely by LG Life Sciences (LGLS). In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey. A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to The Korea Food & Drug Administration (KFDA) in July 2011. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin are now being pursued as of Mar., 2012.


Preclinical Studies

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Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

See also

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[1] [2] [3] [4] [5]

References

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  1. ^ Kim SE, Yi S, Shin KH, Kim TE, Kim MJ, Kim YH, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (2012). "Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444and pioglitazone in healthy volunteers". Int J Clin Pharmacol Ther. 50 (1): 17–23. doi:10.5414/cp201568. PMID 22192641. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Rhee EJ, Lee WY, Yoon KH, Yoo SJ, Lee IK, Baik SH, Kim YK, Lee MK, Park KS, Park JY, Cha BS, Lee HW, Min KW, Bae HY, Kim MJ, Kim JA, Kim DK, Kim SW (2010). "A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes". Diabetes Obes Metab. 12 (12): 1113–1119. doi:10.1111/j.1463-1326.2010.01303.x. PMID 20977584. S2CID 25176783. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Lim KS, Cho JY, Kim BH, Kim JR, Kim HS, Kim DK, Kim SH, Yim HJ, Lee SH, Shin SG, Jang IJ, Yu KS (2009). "Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers". Br J Clin Pharmacol. 68 (6): 883–890. doi:10.1111/j.1365-2125.2009.03376.x. PMC 2810799. PMID 20002082. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ (2008). "Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study". Clin Ther. 30 (10): 1817–1830. doi:10.1016/j.clinthera.2008.10.013. PMID 19014837. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Dal-Mi Hwang, Sung-Ho Kim, Min-Kyung Yoon, O Hwan Kwon, Ki Dong Koo, Changhee Min, Sung-Hack Lee, Jaeick Lee, Chang-Seok Lee, Hyeon Joo Yim (2008). "LC15-0444 is a novel, potent, selective, and orally active dipeptidyl peptidase IV inhibitor" (PDF). American Diabetes Association 68th Scientific Sessions. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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Category:Dipeptidyl peptidase-4 inhibitors Category:LG Group


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