title: SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors.
abstract: A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
authors.affiliation: Department of Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. gang.zhou@merck.com
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Ting
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.forename: Jianhua
authors.initials: J
authors.lastname: Cao
authors.forename: David W
authors.initials: DW
authors.lastname: Kim
authors.forename: Rongze
authors.initials: R
authors.lastname: Kuang
authors.forename: Joe F
authors.initials: JF
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Schwerdt
authors.forename: Heping
authors.initials: H
authors.lastname: Wu
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Zych
authors.forename: Jinhai
authors.initials: J
authors.lastname: Yang
authors.forename: Sang
authors.initials: S
authors.lastname: Lam
authors.forename: Samuel
authors.initials: S
authors.lastname: Wainhaus
authors.forename: Todd A
authors.initials: TA
authors.lastname: Black
authors.forename: Paul M
authors.initials: PM
authors.lastname: McNicholas
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.forename: Scott S
authors.initials: SS
authors.lastname: Walker
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D041221:Candida glabrata / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011724:Pyridazines; D005964:Glucosyltransferases; C040232:glucan synthase