Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a ß-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity.
J Med Chem
; 56(11): 4597-610, 2013 Jun 13.
Article
en En
| MEDLINE
| ID: mdl-23662903
ABSTRACT
Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxazepinas
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Inhibidores de las Quinasa Fosfoinosítidos-3
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Imidazoles
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Antineoplásicos
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos