Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 22, 2010, Pages 6739-6743

  Belanger, David B ^a   Williams, Michael J ^a   Curran, Patrick J ^a   Mandal, Amit K ^a   Meng, Zhaoyang ^a   Rainka, Matthew P ^b   Yu, Tao ^a   Shih, Neng Yang ^a   Siddiqui, M Arshad ^a   Liu, Ming ^a   Tevar, Seema ^a   Lee, Suining ^a   Liang, Lianzhu ^a   Gray, Kimberly ^a   Yaremko, Bohdan ^a   Jones, Jennifer ^a   Smith, Elizabeth B ^a   Prelusky, Dan B ^a   Basso, Andrea D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

Aurora kinase inhibitors; Imidazo 1,2 a pyrazine; Oral bioavailability; Tumor xenograft mouse model

Indexed keywords

AURORA A KINASE; AURORA B KINASE; AURORA C KINASE; AURORA KINASE INHIBITOR; CHECKPOINT KINASE 1; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 4; PROTEIN KINASE LCK; VASCULOTROPIN RECEPTOR 2;

ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; DRUG BIOAVAILABILITY; DRUG CROSS REACTIVITY; DRUG INHIBITION; DRUG POTENCY; DRUG STRUCTURE; HUMAN; IC 50; MOUSE; NONHUMAN; RAT; REACTION OPTIMIZATION; TREATMENT DURATION; TUMOR XENOGRAFT;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; FEMALE; HUMANS; IMIDAZOLES; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRAZINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77958068350     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.140     Document Type: Article

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20. The absolute configuration of alcohol 24 was not determined.
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22. Preparative SFC was performed on a Thar SuperPure SFC-350 instrument and a ChiralPak AS-H column 50 × 250 mm with 25% isopropanol/0.2% diethylamine as eluent (flow rate = 250 g/min; back pressure = 225 bar; concentration = 16 mg/mL). The absolute configuration of the amine 25 was determined by X-ray crystal structural analysis.
23. Compound 25 was designed for oral dosing, but equilibrium solubility studies showed that it was suitable for dosing by intravenous injection (solubility in 20 mM Acetate buffer, pH4 = 4.66 mg/mL).
24. 3, mice were randomly grouped into treatment groups (n = 10). Tumor volumes and body weights were measured twice a week throughout the study using calipers and calculated by the formula (width × length × height) × 6/π. Statistically significant differences were determined by the multiple comparison one way ANOVA (Turkey's test) at the 95% confidence level using GraphPad Prism. All animal studies were carried out in accordance with institutional guidelines and the NIH Guide for the Care and Use of Laboratory Animals.