LFHP-1c is a PGAM5 inhibitor (antagonist) with neuro-protection activity in ischemic stroke. LFHP-1c protects BBB (blood-brain barrier) integrity from ischemic damage. LFHP-1c binds to PGAM5 in endothelial cells, inhibits PGAM5 phosphatase activity, and inhibits the interaction between PGAM5 and NRF2. LFHP-1c is protective in vitro and in vivo.

Physicochemical Properties

Molecular Formula	C55H64N6O4
Molecular Weight	873.134473800659
Exact Mass	872.498
CAS #	2102347-47-5
PubChem CID	168355614
Appearance	White to off-white solid powder
LogP	11.7
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	23
Heavy Atom Count	65
Complexity	1460
Defined Atom Stereocenter Count	0
InChi Key	OITTXMIOSJEXLY-UHFFFAOYSA-N
InChi Code	InChI=1S/C55H64N6O4/c1-6-8-28-50(65-39(4)62)44-23-14-16-25-46(44)55(64)57-34-20-12-10-9-11-19-33-56-54(63)45-24-15-13-22-43(45)41-31-29-40(30-32-41)37-61-49-36-42(35-38(3)52(49)59-51(61)21-7-2)53-58-47-26-17-18-27-48(47)60(53)5/h13-18,22-27,29-32,35-36,50H,6-12,19-21,28,33-34,37H2,1-5H3,(H,56,63)(H,57,64)
Chemical Name	1-[2-[8-[[2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoyl]amino]octylcarbamoyl]phenyl]pentyl acetate
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In rat brain microvascular endothelial cells (rBMECs), treatment with LFHP-1c (1, 2 or 5 μmol/L; 9 h) followed by hypoxia enhanced NRF2 protein expression and encouraged NRF2 nuclear translocation [1].
ln Vivo	In rats, LFHP-1c (5 mg/kg; i.v.; 2 doses) inhibits disruption of the blood brain barrier after temporary middle cerebral artery occlusion (tMCAO)[1]. Through the PGAM5-NRF2 axis, LFHP-1c (3 mg/kg, 1 mL/kg; intravenous injection; 8 doses) reduces cerebral ischemia damage in the fascicularis tMCAO model[1].
Cell Assay	Immunofluorescence[1] Cell Types: Primary rat brain microvascular endothelial cells (rBMECs) Tested Concentrations: 2 μmol/L Incubation Duration: 1 h Experimental Results: Bound to PGAM5, to facilitate nuclear translocation of NRF2.
Animal Protocol	Animal/Disease Models: Nonhuman primate Macaca fascicularis model with tMCAO[1] Doses: 3 mg/kg, 1 mL/kg Route of Administration: IV; at 4 h, 1, 2, 3, 4, 5, 6 and 7 days after tMCAO onset. Experimental Results: decreased infarct volume, brain edema and neurological deficits in Transient MCAO model in M. fascicularis. Animal/Disease Models: SD rats (230-250 g)[1] Doses: 1 mg/kg, 5 mg/kg in 0.5 mL volume Route of Administration: IV; injected at 4 or 12 h after ischemia onset, and then injected another time at 24 h post-ischemia Experimental Results: Dose-dependently protected rat brains against ischemia/reperfusion injury at 72 h after ischemia onset with a moderate therapeutic window. Prevented BBB disruption and attenuated endothelial inflammation in rat cerebral microvessels at 72 h after ischemia onset.
References	[1]. A novel PGAM5 inhibitor LFHP-1c protects blood-brain barrier integrity in ischemic stroke. Acta Pharm Sin B. 2021 Jul;11(7):1867-1884.

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (114.53 mM)

Solubility (In Vivo)

Solubility in Formulation 1: 2.5 mg/mL (2.86 mM) in 10% DMSO 20% HS-15 70% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.1453 mL	5.7265 mL	11.4530 mL
	5 mM	0.2291 mL	1.1453 mL	2.2906 mL
	10 mM	0.1145 mL	0.5727 mL	1.1453 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.