Anagliptin hydrochloride CAS#: 1359670-56-6

Usage And Synthesis

Uses

Anagliptin (SK-0403) hydrochloride is a highly selective, potent, orally active inhibitor of dipeptidyl peptidase 4 (DPP-4), with an IC50 of 3.8 nM, and less selective at DPP-8 and DDP-9 with IC50s of 68 nM and 60 nM, respectively[1].

in vivo

Anagliptin (SK-0403) (0.3%; in diet; 16 weeks) reduces atherosclerotic lesion and does not increase the number of circulating EPCs in apoliporotein E (apoE)-deficient mice^[2].
Anagliptin (0.3%; in diet; 4 weeks) exhibits a lipid‐lowering effect in a hyperlipidemic mice model^[3].

Animal Model:	Male apoliporotein E (apoE)-deficient mice^[2]
Dosage:	0.3%
Administration:	In diet, 16 weeks
Result:	Reduced DPP-4 activity in the plasma as expected and did not affect food consumption or body weight gain. Significantly reduced total cholesterol level, especially VLDL and LDL-C without affecting triglyceride level. Also decreased the α-SMA-positive area within the individual plaque.

Animal Model:	Male low‐density lipoprotein receptor‐deficient mice (B6.129S7‐Ldlr^tm1Her/J)^[3]
Dosage:	0.3%
Administration:	In diet, 4 weeks
Result:	Significantly decreased the plasma total cholesterol (14% reduction) and triglyceride levels (27% reduction). Significantly decreased low‐density lipoprotein cholesterol and very low‐density lipoprotein cholesterol. Sterol regulatory element‐binding protein‐2 messenger ribonucleic acid expression level was significantly decreased at night.

Animal Model:

Male Sprague–Dawley rats and Beagle dogs^[1]

Dosage:

0.2, 0.5, 1 and 10 mg/kg

Administration:

Oral or intravenous administration (Pharmacokinetic Studies)

Result:

Selected PK parameters of Anagliptin hydrochloride in rats and dogs^[1]

Compound	Species	CL_tot (l/h/kg)	V_dss (l/h/kg)	C_max^c (ng/ml)	T_max^c (h)	T_1/2 (h)	AUC (ng/h/ml)	BA (%)
Anagliptin hydrochloride^a	Rat	2.00 (iv)	0.68 (iv)	309 (62) (po)	0.8 (2.3) (po)	1.9 (po)	1160 (po)	23 (po)
	Dog	0.65 (iv)	0.83 (iv)	261 (po)	1.5 (po)	1.0 (po)	824 (po)	100 (po)

^aAnagliptin hydrochloride dose in rats, 1 mg/kg, iv (n = 3); 10 mg/kg, po (n = 3). 4a dose in dogs, 0.2 mg/kg, iv (n = 3); 0.5 mg/kg, po (n = 2). ^cValues in parentheses were obtained at a dose of 3 mg/kg (n = 3).

IC 50

DPP-4: 3.8 nM (IC₅₀); DPP-8: 68 nM (IC₅₀); DPP-9: 60 nM (IC₅₀)

References

[1] Kato N, et al. Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor. Bioorg Med Chem. 2011 Dec 1;19(23):7221-7. DOI:10.1016/j.bmc.2011.09.043
[2] Ervinna N, et al. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology. 2013 Mar;154(3):1260-70. DOI:10.1210/en.2012-1855
[3] Yano W, et al. Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice. J Diabetes Investig. 2017 Mar;8(2):155-160. DOI:10.1111/jdi.12593

Anagliptin hydrochloride

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