title: Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors.
abstract: The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.
authors: Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. Michael
authors: Yan
authors: Y
authors: Shi
authors: Stephen P
authors: SP
authors: O'Connor
authors: Doree
authors: D
authors: Sitkoff
authors: Jing
authors: J
authors: Zhang
authors: Mengxiao
authors: M
authors: Shi
authors: Sharon N
authors: SN
authors: Bisaha
authors: Ying
authors: Y
authors: Wang
authors: Chi
authors: C
authors: Li
authors: Zheming
authors: Z
authors: Ruan
authors: R Michael
authors: RM
authors: Lawrence
authors: Herbert E
authors: HE
authors: Klei
authors: Kevin
authors: K
authors: Kish
authors: Eddie C-K
authors: EC
authors: Liu
authors: Steve M
authors: SM
authors: Seiler
authors: Liang
authors: L
authors: Schweizer
authors: Thomas E
authors: TE
authors: Steinbacher
authors: William A
authors: WA
authors: Schumacher
authors: Jeffrey A
authors: JA
authors: Robl
authors: John E
authors: JE
authors: Macor
authors: Karnail S
authors: KS
authors: Atwal
authors: Philip D
authors: PD
authors: Stein
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D007769:Lactams / Q000737:chemistry; D008968:Molecular Conformation; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007769:Lactams; D010881:Piperidones; D015842:Serine Proteinase Inhibitors; C511520:valerolactam; D015951:Factor Xa