Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.
Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.
Lumma
W C
WC
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Witherup
K M
KM
Tucker
T J
TJ
Brady
S F
SF
Sisko
J T
JT
Naylor-Olsen
A M
AM
Lewis
S D
SD
Lucas
B J
BJ
Vacca
J P
JP
D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000991:Antithrombins; D001559:Benzhydryl Compounds; C111675:L 373722; C111674:L 377009; D011758:Pyrroles; D013917:Thrombin