The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase.
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Takle
Andrew K
AK
Department of Medicinal Chemistry, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Andy.K.Takle@gsk.com
Bamford
Mark J
MJ
Davies
Susannah
S
Davis
Robert P
RP
Dean
David K
DK
Gaiba
Alessandra
A
Irving
Elaine A
EA
King
Frank D
FD
Naylor
Antoinette
A
Parr
Christopher A
CA
Ray
Alison M
AM
Reith
Alastair D
AD
Smith
Beverley B
BB
Staton
Penelope C
PC
Steadman
Jon G A
JG
Stean
Tania O
TO
Wilson
David M
DM
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D020521:Stroke / Q000188:drug therapy; D013329:Structure-Activity Relationship
D005663:Furans; D007093:Imidazoles; D007189:Indans; C530671:L-779,450; D011725:Pyridines; C508204:SB-590885; C530670:SB-699393; D048493:Proto-Oncogene Proteins B-raf