Heterocyclic core analogs of a direct thrombin inhibitor.
Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.
Merck Research Laboratories, Rahway, NJ, USA. Electronic address: timblizzard@comcast.net.
Timothy A
TA
Blizzard
Albany Molecular Research, Singapore Research Center, Singapore.
Sanjay
S
Singh
Albany Molecular Research, Singapore Research Center, Singapore.
Basanagoud
B
Patil
Albany Molecular Research, Singapore Research Center, Singapore.
Naresh
N
Chidurala
Albany Molecular Research, Singapore Research Center, Singapore.
Venukrishnan
V
Komanduri
Albany Molecular Research, Singapore Research Center, Singapore.
Samarpita
S
Debnath
Albany Molecular Research, Singapore Research Center, Singapore.
Sergei
S
Belyakov
Merck Research Laboratories, Rahway, NJ, USA.
Alejandro
A
Crespo
Merck Research Laboratories, Rahway, NJ, USA.
Alice
A
Struck
Merck Research Laboratories, Rahway, NJ, USA.
Marc
M
Kurtz
Merck Research Laboratories, Rahway, NJ, USA.
Judyann
J
Wiltsie
Merck Research Laboratories, Rahway, NJ, USA.
Xun
X
Shen
Merck Research Laboratories, Rahway, NJ, USA.
Lisa
L
Sonatore
Merck Research Laboratories, Rahway, NJ, USA.
Marta
M
Arocho
Merck Research Laboratories, Rahway, NJ, USA.
Dale
D
Lewis
Merck Research Laboratories, Rahway, NJ, USA.
Martin
M
Ogletree
Merck Research Laboratories, Rahway, NJ, USA.
Tesfaye
T
Biftu
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D013917:Thrombin
Anti-thrombotic; DTI; Thrombin inhibitor; Thrombosis