title: Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.
abstract: 6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
authors.affiliation: Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. sue.m.westaway@gsk.com
authors.forename: Susan M
authors.initials: SM
authors.lastname: Westaway
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thompson
authors.forename: Harshad K
authors.initials: HK
authors.lastname: Rami
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Leontine S
authors.initials: LS
authors.lastname: Trouw
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: Jon T
authors.initials: JT
authors.lastname: Seal
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Medhurst
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Lappin
authors.forename: James
authors.initials: J
authors.lastname: Biggs
authors.forename: James
authors.initials: J
authors.lastname: Wright
authors.forename: Sandra
authors.initials: S
authors.lastname: Arpino
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Jerman
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cryan
authors.forename: Vicky
authors.initials: V
authors.lastname: Holland
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Winborn
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Gunthorpe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002211:Capsaicin / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: C540067:6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide; D052160:Benzothiazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D009536:Niacinamide; D002211:Capsaicin