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.
Lesuisse
Dominique
D
Medicinal Chemistry, Sanofi-aventis, 13 Quai Jules Guesde, 94300 Vitry-sur-Seine, France. dominique.lesuisse@sanofi-aventis.com
Tiraboschi
Gilles
G
Krick
Alain
A
Abecassis
Pierre-Yves
PY
Dutruc-Rosset
Gilles
G
Babin
Didier
D
Halley
Frank
F
Châtreau
Fabienne
F
Lachaud
Sylvette
S
Chevalier
Alain
A
Quarteronet
Dominique
D
Burgevin
Marie-Claude
MC
Amara
Céline
C
Bertrand
Philippe
P
Rooney
Thomas
T
D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D047428:Protein Kinase Inhibitors; D019388:Cytochrome P-450 CYP1A2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3