title: Fused bicycles as arylketone bioisosteres leading to potent, orally active thiadiazole H3 antagonists.
abstract: A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
authors.affiliation: Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. dong.xiao@merck.com
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
authors.forename: Michael
authors.initials: M
authors.lastname: Sofolarides
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: Robert E
authors.initials: RE
authors.lastname: West
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Williams
authors.forename: Ren-Long
authors.initials: RL
authors.lastname: Wu
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.forename: Christopher
authors.initials: C
authors.lastname: Sondey
authors.forename: Jean
authors.initials: J
authors.lastname: Lachowicz
authors.forename: Walter A
authors.initials: WA
authors.lastname: Korfmacher
mesh_terms: D000284:Administration, Oral; D000818:Animals; D054828:Histamine H3 Antagonists / Q000493:pharmacokinetics*; D007659:Ketones; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D054828:Histamine H3 Antagonists; D007659:Ketones; D013830:Thiadiazoles