Non-covalent thrombin inhibitors featuring P3-heterocycles with P1-bicyclic arginine surrogates.
Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa approximately non-basic-8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.
Cui
Jingrong Jean
JJ
Department of Medicinal Chemistry, Corvas International, Inc., 3030 Science Park Road, San Diego, CA 92121, USA.
Araldi
Gian-Luca
GL
Reiner
John E
JE
Reddy
Komandla Malla
KM
Kemp
Scott J
SJ
Ho
Jonathan Z
JZ
Siev
Daniel V
DV
Mamedova
Lala
L
Gibson
Tony S
TS
Gaudette
John A
JA
Minami
Nathaniel K
NK
Anderson
Susanne M
SM
Bradbury
Annette E
AE
Nolan
Thomas G
TG
Semple
J Edward
JE
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007202:Indicators and Reagents; D013917:Thrombin