The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 15, 2008, Pages 4373-4376

  Takle, Andrew K ^a   Bamford, Mark J ^a   Davies, Susannah ^a   Davis, Robert P ^a   Dean, David K ^a   Gaiba, Alessandra ^a   Irving, Elaine A ^a   King, Frank D ^a   Naylor, Antoinette ^a   Parr, Christopher A ^a   Ray, Alison M ^a   Reith, Alastair D ^a   Smith, Beverley B ^a   Staton, Penelope C ^a   Steadman, Jon G A ^a   Stean, Tania O ^a   Wilson, David M ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

B Raf; Furan; Indanone oxime; Kinase; Stroke

Indexed keywords

B RAF KINASE; ENZYME INHIBITOR; FURAN DERIVATIVE; L 779450; MITOGEN ACTIVATED PROTEIN KINASE; NERVE GROWTH FACTOR; SB 590885; SB 699393; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BLOOD BRAIN BARRIER; CONCENTRATION RESPONSE; DRUG CLEARANCE; DRUG IDENTIFICATION; DRUG INHIBITION; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; IN VIVO STUDY; NERVE CELL CULTURE; NEUROPROTECTION; NONHUMAN; PROTEIN PHOSPHORYLATION; RAT; STROKE; STRUCTURE ACTIVITY RELATION; THERAPY EFFECT; TREATMENT OUTCOME; TREATMENT RESPONSE;

ANIMALS; CENTRAL NERVOUS SYSTEM; FURANS; IMIDAZOLES; INDANS; MOLECULAR STRUCTURE; PROTO-ONCOGENE PROTEINS B-RAF; PYRIDINES; RATS; STROKE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 47749088184     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.06.070     Document Type: Article

References (16)

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8. PC12 cells were pretreated with compounds for 60 min prior to stimulation with NGF. After 10 min cells were lysed and the lysates separated by SDS-PAGE. Following transfer to nitrocellulose membranes, levels of phosphorylated-ERK1/2 were determined following antibody probing. Pretreatment with 3 μM L-779,540 (2) routinely caused approx. 90% inhibition of NGF-stimulated ERK1/2 phosphorylation.
9. For details of the B-Raf fluorescent ligand binding assay (FP) and the OGD in vitro neuroprotection assay, see Dean, D. K.; Takle, A. K.; Wilson, D. M. PCT Int. Appl. WO 02/24680.
10. Molecular polar surface area (PSA) has long been recognised as a contributing factor to the brain penetration of drug-like molecules. See. Kelder J., Grootenhuis P.D.J., Bayada D.M., Delbressine L.P.C., and Plemen J.-P. Pharm. Res. 16 (1999) 1514
11. PSA values quoted in this paper are calculated using '2D' methods. See. Ertl P., Rohde B., and Selzer P. J. Med. Chem. 43 (2000) 3714
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13. Rats were subjected to a cold water swim (18 °C) for 10 min. The test animals were then sacrificed, the brains removed, dissected and hippocampal phospho-ERK levels assessed by Western blotting. Test compounds were administered as an iv bolus 5 min prior to the cold water swim.
14. See Ref. 3, and references therein, for details of the rat, permanent middle cerebral artery occlusion model of stroke.
15. 1H NMR and LC/MS data in full agreement with their proposed structures. Oximes were isolated as mixtures of E and Z isomers in which the E isomer predominated. For experimental details of the synthesis of SB-699393 (17) see Bamford, M. J.; Dean, D. K.; Naylor, A.; Takle, A. K.; Wilson, D. M. PCT Int. Appl. WO 03/022840.
16. Precedence exists for the regioselective coupling of 2,3-dihalo-substituted furans, see, for example,. Bach T., and Kruger L. Eur. J. Org. Chem. (1999) 2045 Nonetheless, the structure of 22 was also confirmed by HMBC NMR spectroscopy