Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics

From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.

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Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2344-2349
Hauptverfasser:	Lesuisse, Dominique, Tiraboschi, Gilles, Krick, Alain, Abecassis, Pierre-Yves, Dutruc-Rosset, Gilles, Babin, Didier, Halley, Frank, Châtreau, Fabienne, Lachaud, Sylvette, Chevalier, Alain, Quarteronet, Dominique, Burgevin, Marie-Claude, Amara, Céline, Bertrand, Philippe, Rooney, Thomas
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Cytochrome P-450 CYP1A2 - metabolism Cytochrome P-450 CYP1A2 Inhibitors Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Humans Mice Models, Molecular Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology
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Beschreibung
Zusammenfassung:	From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2010.01.132