The design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors.
The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.
Novartis Horsham Research Centre, West Sussex, UK.
J
J
Hayler
P D
PD
Kane
D
D
LeGrand
F
F
Lugrin
K
K
Menear
R
R
Price
M
M
Allen
X
X
Cockcroft
J
J
Ambler
K
K
Butler
K
K
Dunnet
A
A
Mitchelson
M
M
Talbot
M
M
Tweed
N
N
Wills
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D010314:Partial Thromboplastin Time; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D013927:Thrombosis / Q000188:drug therapy; D014357:Trypsin / Q000378:metabolism
D000991:Antithrombins; C416077:CGH 752; D013449:Sulfonamides; D013844:Thiazoles; D002918:Chymotrypsin; D014357:Trypsin; D005341:Fibrinolysin; D000409:Alanine