Uses
The racemic mixture of an aqueous soluble (at least 50 µg/mL or 140 µM at pH 6.5) pyridinyl-4H-benzopyran compound that inhibits insulin-regulated (IRAP) aminopeptidase activity by competing against substrate for IRAP extracellular catalytic site binding (Ki = 0.48 µM; using 25 µM Leu-AMC as substrate) with concomitant interaction with active site zinc via its acetamide, while displaying little potency against glucose-6-phosphatase, aminopeptidase N, ACE1, leukotriene A4 hydrolase, or ER-associated aminopeptidases 1 & 2 (≤13% inhibition at 100 µM). Reported to boost 1 mM dibutyryl cAMP-evoked glucose uptake in cultured rat hippocampal slices (68% higher uptake in 5 min than dbcAMP alone without 100 nM HFI-419) in vitro and exhibit in vivo memory-enhancing efficacay in an object recognition test when administered directly into the cerebral lateral ventricle of rats via a cannula implant (0.1 or 1.0 nmol/2 µL/rat). HFI-419 is reported to hydrolyze into slightly less potent HFI-142 (Ki = 2.0 µM) after i.v. (plasma t1/2 = 11 min; 2 mg/kg) or i.p (plasma t1/2 = 4.6 h; 10 mg/kg) injection in rats, although HFI-142 is more stable and likely exhibits better blood-brain permeability (Blood:Brain HFI-142 ratio = 3.36 and 0.38, respectively, 0.5 and 4 h post single 3 mg HFI-419/kg i.v. injection).
