title: Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors.
abstract: An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
authors.affiliation: Bristol-Myers Squibb Research & Development, P.O. Box 5400, Princeton, New Jersey 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: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Eddie C-K
authors.initials: EC
authors.lastname: Liu
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hartl
authors.forename: Steve M
authors.initials: SM
authors.lastname: Seiler
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Sonia
authors.initials: S
authors.lastname: Youssef
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Steinbacher
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Nyeemah
authors.initials: N
authors.lastname: Grazier
authors.forename: Andrew
authors.initials: A
authors.lastname: Pudzianowski
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.forename: Lorell
authors.initials: L
authors.lastname: Discenza
authors.forename: Joseph
authors.initials: J
authors.lastname: Yanchunas
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.forename: Karnail S
authors.initials: KS
authors.lastname: Atwal
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015951:Factor Xa / Q000187:drug effects; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D014688:Venoms / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D007211:Indoles; D014688:Venoms; D015951:Factor Xa