Benzamide, N-(2-aminophenyl)-4-[[(3E)-2-oxo-3-(2-pyridinylmethylene)-1-piperidinyl]methyl]-

Product NameBenzamide, N-(2-aminophenyl)-4-[[(3E)-2-oxo-3-(2-pyridinylmethylene)-1-piperidinyl]methyl]-
CAS1916505-13-9
MFC25H24N4O2
MW412.48
EINECS
MOL File1916505-13-9.mol

Chemical Properties

Boiling point	625.4±55.0 °C(Predicted)
Density	1.311±0.06 g/cm3(Predicted)
pka	13.12±0.70(Predicted)

Usage And Synthesis

Uses

HDAC-IN-31 is a potent, selective and orally active HDAC inhibitor with IC50s of 84.90, 168.0, 442.7, >10000 nM for HDAC1, HDAC2, HDAC3, HDAC8, respectively. HDAC-IN-31 induces apoptosis and cell cycle arrests at G2/M phase. HDAC-IN-31 shows good antitumor efficacy. HDAC-IN-31 has the potential for the research of diffuse large B-cell lymphoma[1].

in vivo

HDAC-IN-31 (2 mg/kg for i.v.; 10, 100 mg/kg for p.o.) shows good bioavailability with a significant dose dependent manner^[1].
HDAC-IN-31 (50, 100 mg/kg; p.o, daily for 21 consecutive days) shows good antitumor efficacy in a TMD-8 xenograft model without obvious toxicity^[1].
Pharmacokinetic Parameters of HDAC-IN-31 in mice^[1].

Parameters	Unit	24 g (25 mg/kg)
C_max	ng·h·mL^-1	3100±231
T_1/2(po)	h	4.4±0.3
AUC_0-inf(iv)	ng·h·mL^-1	1040±142
AUC_0-inf(po)	ng·h·mL^-1	5180±252
MRT_PO	h	2.6±0.4
F	%	39.9±2.1

ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o.^[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models^[1].

Parameters	Unit	po (25 mg/kg)	po (50 mg/kg)	po (100 mg/kg)
C_max	ng·h·mL^-1	1700±317	14700±1024	10700±1001
AUC_0-t	ng·h·mL^-1	1220±242	9710±314	9740±230
AUC_0-inf	ng·h·mL^-1	1230±165	9730±341	9770±332
MRT_0-t	h	0.750±0.043	0.812±0.023	1.43±0.56
MRT_0-inf	h	0.805±0.086	0.821±0.041	1.51±0.32

Mouse; 25, 50, 100 mg/kg for p.o.^[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models^[1].

PK parameters	Unit	iv (2 mg/kg)	po (10 mg/kg)	po (100 mg/kg)
C_max	ng·h·mL^-1		3960±413	58300±1352
T_1/2	h	0.427±0.016	1.31±0.27	1.63±0.52
AUC_0-inf	ng·h·mL^-1	1250±132	2670±286	57200±1047
MRT	h	0.402±0.032	0.919±0.052	0.897±0.041
CL	mL·kg·min^-1	27.2±1.2
F	%		45.6±1.2	91.8±2.3

ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o.^[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models^[1].

PK parameters	Unit	Monkey	Dog
		iv (1 mg/kg)	po (10 mg/kg)	iv (1 mg/kg)	po (10 mg/kg)
C_max	ng·h·mL^-1		8520±301		4740±243
T_1/2	h	4.31±0.56	9.14±0.32	1.65±0.41	1.51±0.33
AUC_0-inf	ng·h·mL^-1	15700±1842	53200±1241	2550±365	15100±2004
MRT	h	3.41±0.12	8.28±0.32	2.26±0.41	2.71±0.32
CL	mL·kg·min^-1	1.35±0.21		6.72±0.35
Vd_ss	L·kg^-1	0.34±0.22		0.55±0.04
F	%		27.6±2.1		58.9±1.2

Dogs and monkeys; 1 mg/kg for i.v., 10 mg/kg for p.o. for monkey; 1 mg/kg for i.v., 10 mg/kg for p.o. for dog^[1].

Animal Model:	ICR mice^[1]
Dosage:	2 mg/kg for i.v.; 25 mg/kg for p.o.(DMSO/PEG200/saline = 20:20:60, v/v/v)
Administration:	I.v. or p.o.
Result:	Showed high oral bioavailability (F=40%).

Animal Model:	Mouse^[1]
Dosage:	25, 50, 100 mg/kg
Administration:	P.o.
Result:	Did not exhibit a significant dose dependent for oral administration.

Animal Model:	ICR mice^[1]
Dosage:	2, 10, 100 mg/kg (into the form of hydrochloride)
Administration:	2 mg/kg for i.v.; 10, 100 mg/kg for p.o.
Result:	Showed good bioavailability with a significant dose dependent.

Animal Model:	Dogs and monkeys^[1]
Dosage:	1, 10 mg/kg
Administration:	1 mg/kg for i.v.; 10 mg/kg for p.o.
Result:	Showed good pharmacokinetic characteristics for different species.

Animal Model:	5-6 weeks, female CB.17 SCID mice (TMD-8 tumor xenografts)^[1]
Dosage:	50, 100 mg/kg
Administration:	P.o, daily for 21 consecutive days
Result:	Inhibited the tumor growth with the inhibition rate of 77% and had no significant effect on the internal organs of mice at 100 mg/kg/d.

IC 50

HDAC1: 84.90 nM (IC₅₀); HDAC2: 168.0 nM (IC₅₀); HDAC3: 442.7 nM (IC₅₀); HDAC8: >10000 nM (IC₅₀)

References

[1] Cui H,et al. Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics. Eur J Med Chem. 2022 Feb 5;229:114049. DOI:10.1016/j.ejmech.2021.114049

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