Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors.
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.
Shi
Yan
Y
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
Sitkoff
Doree
D
Zhang
Jing
J
Han
Wei
W
Hu
Zilun
Z
Stein
Philip D
PD
Wang
Ying
Y
Kennedy
Lawrence J
LJ
O'Connor
Stephen P
SP
Ahmad
Saleem
S
Liu
Eddie C-K
EC
Seiler
Steve M
SM
Lam
Patrick Y S
PY
Robl
Jeffrey A
JA
Macor
John E
JE
Atwal
Karnail S
KS
Zahler
Robert
R
D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors