title: Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors.
abstract: The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Doree
authors.initials: D
authors.lastname: Sitkoff
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Zilun
authors.initials: Z
authors.lastname: Hu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Kennedy
authors.forename: Stephen P
authors.initials: SP
authors.lastname: O'Connor
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Eddie C-K
authors.initials: EC
authors.lastname: Liu
authors.forename: Steve M
authors.initials: SM
authors.lastname: Seiler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Karnail S
authors.initials: KS
authors.lastname: Atwal
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
mesh_terms: D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors