ChemicalBook CAS DataBase List 1844874-26-5

1844874-26-5

Name	D-arabino-Hexitol, 5-amino-2,6-anhydro-1,3,4,5-tetradeoxy-6-C-(2,5-difluorophenyl)-3-[2,6-dihydro-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(4H)-yl]-1,1,1-trifluoro-, (6R)-
CAS	1844874-26-5
Molecular Formula	C18H19F5N4O3S
Molecular Weight	466.43
MOL File	1844874-26-5.mol

Chemical Properties

Boiling point	524.0±60.0 °C(Predicted)
density	1.68±0.1 g/cm3(Predicted)
form	Solid
pka	8.66±0.70(Predicted)
color	White to off-white
InChIKey	GUBOXFWNNXSQNH-GYDUIUCANA-N
SMILES	C([C@H]1O[C@H](C2C=C(F)C=CC=2F)[C@@H](N)C[C@H]1N1CC2=NN(S(=O)(=O)C)C=C2C1)(F)(F)F \|&1:1,3,12,15,r\|

Hazard Information

Uses

Cofrogliptin (HSK7653) (compound 2), a tetrahydropyran derivative, is a potent oral dipeptidyl aminopeptidase 4 (DPP-4) inhibitor with Long-acting antidiabetic efficacy. Cofrogliptin (compound 2) has a great potential for type 2 diabetes mellitus (T2DM) [1].

in vivo

Cofrogliptin (HSK7653) (compound 2) (IV: 0.5 mg/kg; PO: 2 mg/kg) exhibits extremely long half-lives and low rate of reduction of drug concentration after orally administration.
Cofrogliptin (compound 2) (Single, orally, 3 mg/kg, 10 mg/kg, 30 mg/kg) increases of half-lives, has high oral exposure, low i.v. clearance and hepatic microsomal clearance after intravenous dosing.
Cofrogliptin (compound 2) (Single, orally, 10 mg/kg) exhibits longe inhibition time of DPP-4 and decreases HbA1c level at the doses of 3 and 10 mg/kg in ob/ob mice. Cofrogliptin (compound 2) (Single, orally, 10 mg/kg) also has a great potential of biweekly regimen for T2DM as indicated in rhesus monkeys^[2].

Pharmacokinetic Parameters in ICR mice^[2]

	IV(dose: 0.5 mg/kg)			PO(dose: 2 mg/kg)
	CI(mL/min/kg)	V_dss(L/kg)	t_1/2(h)	C_max(ng/mL)	t_1/2(h)	AUC_0-t(ng h/mL)	F%
Omarigliptin	7.39±2.1	1.65±0.27	3.05±0.6	798±122	4.65±1.4	4095±552	95.0±29
Cofrogliptin (compound 2)	2.57±0.09	3.30±0.33	25.6±9.6	352±20	29.9±3.2	7898±873	62.2±6.9

Animal Model:	ob/ob mice^[2]
Dosage:	3 mg/kg, 10 mg/kg, 30 mg/kg
Administration:	Single, orally, 3 mg/kg, 10 mg/kg, 30 mg/kg
Result:	Exhibited strong inhibition capability of plasma DPP-4 in a dose dependent manner.

Animal Model:	rhesus monkeys^[2]
Dosage:	10 mg/kg
Administration:	Single, orally, 10 mg/kg
Result:	Possessed the capability of plasma DPP-4 inhibition over 80% for at least 12 days. Remained the plasma DPP-4 inhibition rates of 76.16% and 43.41%, respectively at the end of second week and third week after administration.

IC 50

DPP-4

References

[1] International Nonproprietary Names for Pharmaceutical Substances (INN)
[2] Chen Zhang, et al. Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. J Med Chem. 2020 Jul 9;63(13):7108-7126. DOI:10.1021/acs.jmedchem.0c00374

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