P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold.
In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).
Nantermet
Philippe G
PG
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. philippe_nantermet@merck.com
Burgey
Christopher S
CS
Robinson
Kyle A
KA
Pellicore
Janetta M
JM
Newton
Christina L
CL
Deng
James Z
JZ
Selnick
Harold G
HG
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Krueger
Julie A
JA
Miller-Stein
Cynthia
C
White
Rebecca B
RB
Wong
Bradley
B
McMasters
Daniel R
DR
Wallace
Audrey A
AA
Lynch
Joseph J
JJ
Yan
Youwei
Y
Chen
Zhongguo
Z
Kuo
Lawrence
L
Gardell
Stephen J
SJ
Shafer
Jules A
JA
Vacca
Joseph P
JP
Lyle
Terry A
TA
D000991:Antithrombins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D011743:Pyrimidines / Q000737:chemistry*
D000991:Antithrombins; D011743:Pyrimidines