Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.
In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
Burgey
Christopher S
CS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_urgey@merck.com
Robinson
Kyle A
KA
Lyle
Terry A
TA
Nantermet
Philippe G
PG
Selnick
Harold G
HG
Isaacs
Richard C A
RC
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Krueger
Julie A
JA
Singh
Rominder
R
Miller-Stein
Cynthia
C
White
Rebecca B
RB
Wong
Bradley
B
Lyle
Elizabeth A
EA
Stranieri
Maria T
MT
Cook
Jacquelynn J
JJ
McMasters
Daniel R
DR
Pellicore
Janetta M
JM
Pal
Swati
S
Wallace
Audrey A
AA
Clayton
Franklin C
FC
Bohn
Dennis
D
Welsh
Denise C
DC
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
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004285:Dogs; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010087:Oxides / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy
C478338:3-amino-6-chloropyrazinone acetamide; D000081:Acetamides; D010087:Oxides; D011719:Pyrazines; D011725:Pyridines; D013917:Thrombin