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1.
Eur J Med Chem ; 156: 180-189, 2018 Aug 05.
Article in English | MEDLINE | ID: mdl-30006163

ABSTRACT

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.


Subject(s)
Dipeptides/metabolism , Drug Carriers/metabolism , Drug Delivery Systems , Intestinal Mucosa/metabolism , Peptide Transporter 1/metabolism , Prodrugs/metabolism , Thioamides/metabolism , Animals , Caco-2 Cells , Dipeptides/chemistry , Drug Carriers/chemistry , Humans , Intestinal Absorption , Male , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Rats , Rats, Sprague-Dawley , Thioamides/chemistry , Xenopus laevis
2.
Bioorg Med Chem Lett ; 22(4): 1770-3, 2012 Feb 15.
Article in English | MEDLINE | ID: mdl-22264480

ABSTRACT

A group of novel synthetic indoloisoquinolines was prepared and its potential as a novel series of small-molecule anti-malarial leads was assessed. The structure-activity relationship on variation of three distinct regions of chemical space was investigated. A lead compound was generated with an activity close to that observed for a known anti-malarial natural product, dihydrousambarensine, that shares the indoloisoquinoline template structure.


Subject(s)
Antimalarials , Indoles/chemistry , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Isoquinolines/chemistry , Molecular Structure , Small Molecule Libraries , Structure-Activity Relationship
3.
J Med Chem ; 53(16): 5942-55, 2010 Aug 26.
Article in English | MEDLINE | ID: mdl-20718493

ABSTRACT

Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.


Subject(s)
Aminopyridines/chemistry , Antineoplastic Agents/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/chemistry , Models, Molecular , Phenols/chemistry , Aminopyridines/chemical synthesis , Crystallography, X-Ray , Databases, Factual , Drug Design , Ligands , Magnetic Resonance Spectroscopy , Phenols/chemical synthesis , Protein Binding , Protein Structure, Tertiary , Resorcinols/chemical synthesis , Resorcinols/chemistry , Structure-Activity Relationship
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