Design and synthesis of potent and selective macrocyclic thrombin inhibitors.
A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.
Nantermet
Philippe G
PG
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. philippe_nanternet@merck.com
Barrow
James C
JC
Newton
Christina L
CL
Pellicore
Janetta M
JM
Young
MaryBeth
M
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Krueger
Julie A
JA
McMasters
Daniel R
DR
Yan
Youwei
Y
Kuo
Lawrence C
LC
Vacca
Joseph P
JP
Selnick
Harold G
HG
D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
D000991:Antithrombins; D011719:Pyrazines; D011392:Proline; D014357:Trypsin; D013917:Thrombin