title: Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain.
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. jameswmyatt@yahoo.co.uk
authors.forename: James W
authors.initials: JW
authors.lastname: Myatt
authors.forename: Mark P
authors.initials: MP
authors.lastname: Healy
authors.forename: Gianpaolo S
authors.initials: GS
authors.lastname: Bravi
authors.forename: Andrew
authors.initials: A
authors.lastname: Billinton
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Kim L
authors.initials: KL
authors.lastname: Matthews
authors.forename: Karamjit S
authors.initials: KS
authors.lastname: Jandu
authors.forename: Wenjing
authors.initials: W
authors.lastname: Meng
authors.forename: Anne
authors.initials: A
authors.lastname: Hersey
authors.forename: David G
authors.initials: DG
authors.lastname: Livermore
authors.forename: Clement B
authors.initials: CB
authors.lastname: Douault
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.forename: James E
authors.initials: JE
authors.lastname: Rowedder
authors.forename: Jason D
authors.initials: JD
authors.lastname: Brown
authors.forename: Nick M
authors.initials: NM
authors.lastname: Clayton
mesh_terms: 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
chemical_list: 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