Pyrazolone based TGFβR1 kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 1, 2010, Pages 326-329

  Guckian, Kevin ^a   Carter, Mary Beth ^a   Lin, Edward Yin Shiang ^a   Choi, Michael ^a   Sun, Lihong ^a   Boriack Sjodin, P Ann ^a   Chuaqui, Claudio ^a   Lane, Benjamin ^a   Cheung, Kam ^a   Ling, Leona ^a   Lee, Wen Cherng ^a  

^a BIOGEN   (United States)

Author keywords

Kinase inhibitors; Pyrazolone; TGF

Indexed keywords

CARBONYL DERIVATIVE; LYSINE; PHOSPHOTRANSFERASE INHIBITOR; PYRAZOLONE; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1 KINASE INHIBITOR; UNCLASSIFIED DRUG; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE; PYRAZOLONE DERIVATIVE; TGF BETA TYPE I RECEPTOR; TGF-BETA TYPE I RECEPTOR; TRANSFORMING GROWTH FACTOR BETA RECEPTOR;

ANIMAL EXPERIMENT; ARTICLE; CATALYSIS; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HYDROGEN BOND; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; ANIMAL; BINDING SITE; CHEMISTRY; DRUG ANTAGONISM; METABOLISM; MOUSE; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ANIMALS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; MICE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRAZOLONES; RATS; RECEPTORS, TRANSFORMING GROWTH FACTOR BETA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 72049090613     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.10.108     Document Type: Article

References (11)

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7. 50s for displacement of a labeled TGFβRI kinase inhibitor, HTS446284, 4-(3-pyridin-2-yl-1H-pyrazol-4-yl)-quinoline6, from purified recombinant TGFβRI kinase domain. Inhibition of cellular TGFβRI activity was determined by incubation of the test compound with HepG2 cells harboring a TGFβ signaling reporter, PAI-luciferase. These assays are described in detail in Ref. 9.
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10. PK parameters were determined by oral and iv administration of compound 33 at 5 mg/kg using 20% captisol as the vehicle. Eight time points were taken per arm and fitting of the curves and calculation of the PK parameters was performed with WinNonlin (Pharsight).
11. To evaluate the impact of ALK5 inhibitors on the TGFβ signaling pathway, Balb/C mice were injected with an adenoviral TGFβ inducible luciferase reporter intravenously. One day following adenoviral reporter administration, mice were first treated with a single oral dose of inhibitors or vehicle, and then challenged with 3 μg of recombinant human TGFβ protein injected into the peritoneal cavity 1 h later. The abilities of ALK5 inhibitors to block TGFβ inducible luciferase reporter expression in the animals were assessed at real-time non-invasively using the bioluminescence animal imaging IVISTM system according to manufacturer instructions (Caliper Life Sciences).