Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain.
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Myatt
James W
JW
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. jameswmyatt@yahoo.co.uk
Healy
Mark P
MP
Bravi
Gianpaolo S
GS
Billinton
Andrew
A
Johnson
Christopher N
CN
Matthews
Kim L
KL
Jandu
Karamjit S
KS
Meng
Wenjing
W
Hersey
Anne
A
Livermore
David G
DG
Douault
Clement B
CB
Witherington
Jason
J
Bit
Rino A
RA
Rowedder
James E
JE
Brown
Jason D
JD
Clayton
Nick M
NM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D020746:Calcium Channels, L-Type; D008024:Ligands; D009437:Neuralgia / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000700:Analgesics; C486060:Cacna2d1 protein, rat; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D008024:Ligands; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; C118531:pyrazolopyridine; C062482:pyridazine