Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.
In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
Young
Mary Beth
MB
Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., WP14-3, Post Office Box 4, Sumneytown Pike, West Point, PA 19486, USA. mary_beth_young@merck.com
Barrow
James C
JC
Glass
Kristen L
KL
Lundell
George F
GF
Newton
Christina L
CL
Pellicore
Janetta M
JM
Rittle
Kenneth E
KE
Selnick
Harold G
HG
Stauffer
Kenneth J
KJ
Vacca
Joseph P
JP
Williams
Peter D
PD
Bohn
Dennis
D
Clayton
Franklin C
FC
Cook
Jacquelynn J
JJ
Krueger
Julie A
JA
Kuo
Lawrence C
LC
Lewis
S Dale
SD
Lucas
Bobby J
BJ
McMasters
Daniel R
DR
Miller-Stein
Cynthia
C
Pietrak
Beth L
BL
Wallace
Audrey A
AA
White
Rebecca B
RB
Wong
Bradley
B
Yan
Youwei
Y
Nantermet
Philippe G
PG
D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry
D001596:Benzylamines; D006571:Heterocyclic Compounds; D011719:Pyrazines; D011725:Pyridines; D013777:Tetrazoles; D013830:Thiadiazoles; D014230:Triazoles; D013917:Thrombin