Development of autotaxin inhibitors: A series of zinc binding triazoles

[Display omitted] •PF-8380 has been used as a template to design a new series of ATX inhibitors.•Reduction of crystallinity was key to improving solubility of the new series.•Selectivity and good oral exposure was achieved with this series.•Compound 12 shows a direct PK-PD relationship with inhibiti...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 28; no. 13; pp. 2279 - 2284
Main Authors:	Thomson, Christopher G., Le Grand, Darren, Dowling, Mark, Brocklehurst, Cara E., Chinn, Colin, Elphick, Lucy, Faller, Michael, Freeman, Mark, Furminger, Vikki, Gasser, Cornelia, Hamadi, Ahmed, Hardaker, Elizabeth, Head, Victoria, Hill, Johan C., Janus, Diana I., Pearce, David, Poulaud, Anne-Sophie, Stanley, Emily, Sviridenko, Lilya
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-07-2018
Subjects:	Administration, Oral Animals Autotaxin inhibition Benzoxazoles - pharmacology Drug Design Drug Stability hERG inhibition Humans Idiopathic pulmonary fibrosis Male Microsomes - metabolism Phosphodiesterase Inhibitors - administration & dosage Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - pharmacokinetics Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - metabolism Piperazines - pharmacology PK/PD Rats, Sprague-Dawley Solubility Triazoles - administration & dosage Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - pharmacology hERG inhibition PK/PD Autotaxin inhibition Idiopathic pulmonary fibrosis Solubility
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Summary:	[Display omitted] •PF-8380 has been used as a template to design a new series of ATX inhibitors.•Reduction of crystallinity was key to improving solubility of the new series.•Selectivity and good oral exposure was achieved with this series.•Compound 12 shows a direct PK-PD relationship with inhibition of production of LPA. A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 – a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration-dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2018.05.030