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Issue 4, 2011
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Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD

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Abstract

Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the PROTOBUILD program and its ability to rapidly produce novel modulators for a well characterized drug target.

Graphical abstract: Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program protobuild

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Publication details

The article was received on 19 May 2010, accepted on 07 Oct 2010 and first published on 15 Dec 2010


Article type: Paper
DOI: 10.1039/C0OB00146E
Citation: Org. Biomol. Chem., 2011,9, 1169-1188
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    Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD

    Y. Bhurruth-Alcor, T. Røst, M. R. Jorgensen, C. Kontogiorgis, J. Skorve, R. G. Cooper, J. M. Sheridan, W. D. O. Hamilton, J. R. Heal, R. K. Berge and A. D. Miller, Org. Biomol. Chem., 2011, 9, 1169
    DOI: 10.1039/C0OB00146E

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