The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position.
A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds with low nanomolar potency and good selectivity for thrombin.
Novartis Horsham Research Centre, West Sussex, UK.
U
U
Baettig
L
L
Brown
D
D
Brundish
C
C
Dell
A
A
Furzer
S
S
Garman
D
D
Janus
P D
PD
Kane
G
G
Smith
C V
CV
Walker
X
X
Cockcroft
J
J
Ambler
A
A
Mitchelson
M D
MD
Talbot
M
M
Tweed
N
N
Wills
D000409:Alanine; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D007610:Kallikreins / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D013844:Thiazoles; D013917:Thrombin / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000991:Antithrombins; D065427:Factor Xa Inhibitors; D010875:Pipecolic Acids; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D001120:Arginine; D007610:Kallikreins; D002918:Chymotrypsin; D014357:Trypsin; D013917:Thrombin; D005341:Fibrinolysin; C031942:argatroban; D000409:Alanine