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Eur J Med Chem
2018 Aug 05;156:180-189. doi: 10.1016/j.ejmech.2018.06.064.
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Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery.
Foley DW
,
Pathak RB
,
Phillips TR
,
Wilson GL
,
Bailey PD
,
Pieri M
,
Senan A
,
Meredith D
.
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The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2 mM. Compounds which showed robust transport in an oocyte trans-stimulation assay were then tested for transcellular transport in Caco-2 cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.
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30006163
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Fig. 1. PepT1 as a drug delivery target. Drugs are attached to the side-chains of the seryl (A) or aspartyl (B) thiodipeptide carriers, directly or via linkers, forming prodrug substrates of PepT1.
Fig. 2. Rationally designed prodrugs to target PepT1 (parent drug in brackets).
Scheme 1. Synthesis of protected aspirin pro-drug. (i) PPh3, triethylene glycol, DIAD, THF, rt, sonication, 15 min (ii) 13 [15], HBTU, DIPEA, DMF, rt, 4 days.
Fig. 3. The Ki of prodrugs 1 and 3 for rabbit PepT1 expressed in Xenopus laevis oocytes.
Fig. 4. Effect of incubation of 10 mM prodrugs on the trans-stimulation efflux of radiolabelled [3H]-D-Phe-L-Gln, compared to the known PepT1 substrate GlyGln.
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