ChemicalBook CAS DataBase List 1364914-72-6

1364914-72-6

Name	LeuRS-IN-1
CAS	1364914-72-6
Molecular Formula	C10H13BClNO3
Molecular Weight	241.48
MOL File	1364914-72-6.mol

Hazard Information

Uses

LeuRS-IN-1 is a potent, orally active M. tuberculosis leucyl-tRNA synthetase (M.tb LeuRS) inhibitor. LeuRS-IN-1 has IC50 and Kd values of 0.06 μM, 0.075 μM for M.tb LeuRS, respectively[1]. LeuRS-IN-1 inhibits human cytoplasmic LeuRS (IC50=38.8 μM), and HepG2 protein synthesis (EC50=19.6 μM)[2].

in vivo

LeuRS-IN-1 (100 mg/kg; orally daily for 14 days) reduces lung CFU value in acute tuberculosis (TB) mice^[1].
LeuRS-IN-1 (33 mg/kg; orally 5 days a week for 4 weeks) reduces lung and spleen CFU values in chronic TB mice^[1].
Murine pharmacokinetic parameters^[1]:

Administration	Dose (mg/kg)	C_max (μg/ml) at 5 min	CL (ml/h/kg)	V_ss?(ml/kg)	MRT (h)	AUC_0-∞ (h · μg/ml)	α-t_1/2 (h) (% AUC)	β-t_1/2 (h) (% AUC)
i.v.	30	13.6	582	3,142	5.4	51.6	0.10 (2)	3.83 (98)

Administration	Dose (mg/kg)	C_max?(μg/ml)	T_max?(h)	AUC_0-24 (h · μg/ml)	Terminal? t_1/2?(h)	Bioavailability (%)?(h · μg/ml)	Mouse PPB (%)
p.o.	30	6.4	0.25	47.5	3.1	9.2	23

Animal Model:	Murine GKO (C57BL/6-Ifngtm1ts) model of acute TB^[1]
Dosage:	100 mg/kg
Administration:	Orally daily for 14 days after 10 days of infection (start) with M. tuberculosis Erdman.
Result:	Reduced lung CFU value in mice.

Animal Model:	Murine BALB/c model of chronic TB infection^[1]
Dosage:	33 mg/kg
Administration:	Orally 5 days a week for 4 weeks after infection with M. tuberculosis Erdman with a low-dose aerosol 21 days prior (start).
Result:	Reduced lung and spleen CFU values in mice.

IC 50

M.tb LeuRS: 0.06 μM (IC₅₀); M.tb LeuRS: 0.075 μM (Kd); human cytoplasmic LeuRS: 38.8 μM (IC₅₀); HepG2 protein synthesis: 19.6 μM (EC₅₀)

References

[1] Palencia A, et al. Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase. Antimicrob Agents Chemother. 2016;60(10):6271-6280. Published 2016 Sep 23. DOI:10.1128/AAC.01339-16
[2] Li X, et al. Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656). J Med Chem. 2017 Oct 12;60(19):8011-8026. DOI:10.1021/acs.jmedchem.7b00631

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