Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders.
Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3β. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3β inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK-3β inhibitors as new tools in the development of new treatments for mood disorders.
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Guido
G
Furlotti
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Maria Alessandra
MA
Alisi
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Nicola
N
Cazzolla
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Patrizia
P
Dragone
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Lucia
L
Durando
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Gabriele
G
Magarò
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Francesca
F
Mancini
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Giorgina
G
Mangano
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Rosella
R
Ombrato
Angelini S.p.A., Angelini Research Center , P.le della Stazione s.n.c., Santa Palomba-Pomezia, 00071 Rome, Italy.
Marco
M
Vitiello
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Andrea
A
Armirotti
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Valeria
V
Capurro
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Massimiliano
M
Lanfranco
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Giuliana
G
Ottonello
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Maria
M
Summa
Drug Discovery and Development Department, Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
Angelo
A
Reggiani
D000255:Adenosine Triphosphate / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D019964:Mood Disorders / Q000188:drug therapy*; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000378:metabolism
D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D016875:tau Proteins; D000255:Adenosine Triphosphate; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3