Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors.
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.
Shi
Yan
Y
Bristol-Myers Squibb Research & Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. yan.shi@bms.com
Sitkoff
Doree
D
Zhang
Jing
J
Klei
Herbert E
HE
Kish
Kevin
K
Liu
Eddie C-K
EC
Hartl
Karen S
KS
Seiler
Steve M
SM
Chang
Ming
M
Huang
Christine
C
Youssef
Sonia
S
Steinbacher
Thomas E
TE
Schumacher
William A
WA
Grazier
Nyeemah
N
Pudzianowski
Andrew
A
Apedo
Atsu
A
Discenza
Lorell
L
Yanchunas
Joseph
J
Stein
Philip D
PD
Atwal
Karnail S
KS
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
D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D007211:Indoles; D014688:Venoms; D015951:Factor Xa