title: A phosphinic acid dipeptide analogue to stabilize peptide drugs during their intranasal absorption.
abstract: A major challenge in intranasal delivery of peptides is to overcome the enzymatic barrier that limits their absorption. Aminopeptidase inhibitors may be useful for improving systemic delivery of peptide drugs administered nasally. A phosphinic acid dipeptide analogue, a transition-state analogue aminopeptidase inhibitor in which the phosphinate moiety exists in a tetrahedral state mimicking peptides during their enzymatic hydrolysis, was synthesized and tested nasally in situ in rats. This inhibitor was found to inhibit greatly the degradation of the model peptide leucine-enkephalin in the nasal perfusate at less than or equal to 2 microM concentrations. The nasal peptidase hydrolytic activity was reversible after exposure to the inhibitor. This inhibitor has the advantage of efficacy at very low concentrations and reversibility of effects.
authors.affiliation: Du Pont Merck Pharmaceutical Co., Wilmington, Delaware 19880-0400.
authors.forename: M A
authors.initials: MA
authors.lastname: Hussain
authors.forename: M S
authors.initials: MS
authors.lastname: Lim
authors.forename: K S
authors.initials: KS
authors.lastname: Raghavan
authors.forename: N J
authors.initials: NJ
authors.lastname: Rogers
authors.forename: R
authors.initials: R
authors.lastname: Hidalgo
authors.forename: C A
authors.initials: CA
authors.lastname: Kettner
mesh_terms: D000042:Absorption; D000281:Administration, Intranasal; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D004743:Enkephalin, Leucine / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010477:Perfusion; D010721:Phosphinic Acids / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004151:Dipeptides; D010721:Phosphinic Acids; D004743:Enkephalin, Leucine