Ayumu Niida

Transport Characteristics of a Novel Peptide Transporter 1 Substrate, Antihypotensive Drug Midodrine, and Its Amino Acid Derivatives

Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2′,5′-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.

Efficient Synthesis of Trifluoromethyl and Related Trisubstituted Alkene Dipeptide Isosteres by Palladium-Catalyzed Carbonylation of Amino Acid Derived Allylic Carbonates

A novel stereoselective synthetic approach to (Z)-trifluoromethylalkene dipeptide isosteres (CF(3)-ADIs) is described. Starting from readily available N-Boc-L-phenylalanine, Phe-Gly type CF(3)-ADIs were obtained through palladium-catalyzed carbonylation of allylic carbonates under CO. While the reaction of N-Boc derivatives proceeds in excellent yields but lower stereoselectivity (E: Z = 62:38-43:57), the reaction of the N, N-diBoc derivative exclusively affords the desired (Z)-isomer in 61% yield. We also present a highly stereoselective synthesis of several Phe-Gly type trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation.

A novel one-pot reaction involving organocopper-mediated reduction/transmetalation/asymmetric alkylation, leading to the diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres

By a novel one-pot reaction sequence involving consecutive organocopper-mediated reduction, transmetalation and asymmetric alkylation, a highly diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres was achieved in good to excellent yields.

Synthesis and Application of (Z)-Alkene- and (E)-Fluoroalkene-Dipeptide Isosteres as cis-Amide Equivalents

Introduction dipeptide isosteres have been developed as nonhydrolyzable peptide-bond bio-isosteres that mimic the planar structure of peptide bonds. Restricted peptide bond (ω-angle) rotations in alkene-type isosteres enable one to investigate the cis or trans conformation of the peptide bonds. The precedented synthetic methods reported for alkene-type dipeptide isosteres preferentially provide trans-amide bond mimics, such as (E)-alkene dipeptide isosteres (ADIs) and (Z)fluoroalkene dipeptide isosteres (FADIs). On the other hand, there have only been a few reports on the synthesis of cis-amide bond mimics possessing (Z)-alkene or (E)fluoroalkene, which limits their application. Recently, we established a widely applicable synthetic method for the synthesis of (Z)-ADI and (E)-FADI using organocopper-mediated reduction of certain α,βunsaturated-δ-lactams possessing a leaving group(s) at the γ-position, followed by ring-opening of the lactams [1]. Herein, we report the use of Phe-Gly-type (Z)-ADI and (E)-FADI in the Fmocbased solid-phase peptide synthesis (SPPS) of peptide derivatives of a GPR54 agonist 1 [H-Amb-Phe-Gly-Leu-Arg-Trp-NH2; Amb = 4-(aminomethyl)benzoic acid], to probe the conformational requirement of its Phe-Gly peptide bond.

Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-one derivatives by organocopper reagents provides novel access to di-, tri- and tetra-substituted alkene dipeptide isosteres

Organocopper-mediated alkylation of β-( N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates has been intensively investigated. Alkylation proceeded regio- and stereoselectively by anti- SN2′ ring-opening to provide a new route to the synthesis of ψ[( E)-CHCH]-, ψ[( E)-CMeCH]- and ψ[( E)-CMeCMe]- type alkene dipeptide isosteres from chiral amino acid derivatives. These resulting agents are potential mimetics of type II and type II′ β-turn substructure.