Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines.
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
Burgey
Christopher S
CS
Departments of Medicinal Chemistry, Biological Chemistry, Drug Metabolism, Molecular Systems, Structural Biology, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_burgey@merck.com
Robinson
Kyle A
KA
Lyle
Terry A
TA
Sanderson
Philip E J
PE
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
Williams
Peter D
PD
Coburn
Craig A
CA
Dorsey
Bruce D
BD
Barrow
James C
JC
Stranieri
Maria T
MT
Holahan
Marie A
MA
Sitko
Gary R
GR
Cook
Jacquelynn J
JJ
McMasters
Daniel R
DR
McDonough
Colleen M
CM
Sanders
William M
WM
Wallace
Audrey A
AA
Clayton
Franklin C
FC
Bohn
Dennis
D
Leonard
Yvonne M
YM
Detwiler
Theodore J
TJ
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 / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D008253:Macaca mulatta; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000081:Acetamides; D000925:Anticoagulants; D011480:Protease Inhibitors; D011719:Pyrazines; D011725:Pyridines; D013917:Thrombin