Dihexa is an orally active, blood-brain barrier-permeable angiotensin IV analog, exhibits high affinity binding hepatocyte growth factor (HGF) with a Kd of 65 pM. Dihexa binds with high affinity to HGF and both dihexa and its parent compound Norleucine 1-AngIV induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Dihexa effectively inhibits HGF dimerization at 1 μM. While dihexa at 1 nM and 10 pM alone does not activate c-Met, it markedly augments the capacity of HGF at 1.25 and 2.5 ng/mL to activate c-Met.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 27 mg/mL|
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.
Benoist CC, et al. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. PMID: 25187433.
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
McCoy AT, et al. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. PMID: 23055539.
|Related c-Met Products|
NPS-1034 is a dual inhibitor of Axl and MET with IC50 values of 10.3 and 48 nM, respectively.
CEP-40783 (RXDX-106) is a potent, selective and orally available inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively.
Savolitinib (volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.
AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor.
S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nmol/L.
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