Dihexa

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.

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Met/HGFR

Research Areas >> Neurological Disease

Kd: 65 pM (HGF)[1]

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. Further, dihexa and Nle1-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. 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[1].

Dihexa has a long circulating half-life. Dihexa exhibits procognitive activity. Dihexa reverses scopolamine-dependent spatial learning deficits. It improves spatial learning in aged rats. Dihexa induces spinogenesis in cultured hippocampal neurons[2].

Rats: Serial dilutions of dihexa in 50% DMSO or water (for dilutions of 50 µg/mL or less) are prepared from the stock used to dose the animals to be used for preparation of a standard curve. 10 µL of each serial dilution is then added to 90 µL of blank plasma for final concentrations of 0.01, 0.02, 0.05, 0.1, 0.2, 1, 10, 20, 50, and 100 µg/mL. 80 µL of each plasma sample is transferred to previously prepared tubes containing 240 µL of ice-cold acetonitrile and vortexed vigorously. 10 µL of isotonic saline containing 100 µg/mL Nle-YI-(6) aminohexanoic amide as an internal standard is added to each sample on ice. The standard-curve plasma samples are then stored at −20°C and further processed alongside the pharmacokinetic study samples[2].

[1]. Benoist CC, et al. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402.

[2]. McCoy AT, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54.

Capmatinib (INCB28060) | Foretinib (GSK1363089) | PHA-665752 | BMS-777607 | Savolitinib | Tivantinib (ARQ 197) | tepotinib | LY2801653 | SGX-523 | DCC-2618 | SU11274 | Ensartinib | CEP-40783 | JNJ-38877605 | AMG-337