Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties.
J Med Chem
; 61(3): 946-979, 2018 02 08.
Article
en En
| MEDLINE
| ID: mdl-29350534
ABSTRACT
CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4+ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4+ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4+ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores CXCR4
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Tetrahidroisoquinolinas
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Descubrimiento de Drogas
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Inhibidores del Citocromo P-450 CYP2D6
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Absorción Fisicoquímica
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos