title: Non-covalent thrombin inhibitors featuring P3-heterocycles with P1-bicyclic arginine surrogates.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Corvas International, Inc., 3030 Science Park Road, San Diego, CA 92121, USA.
authors.forename: Jingrong Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Gian-Luca
authors.initials: GL
authors.lastname: Araldi
authors.forename: John E
authors.initials: JE
authors.lastname: Reiner
authors.forename: Komandla Malla
authors.initials: KM
authors.lastname: Reddy
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Kemp
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Ho
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Siev
authors.forename: Lala
authors.initials: L
authors.lastname: Mamedova
authors.forename: Tony S
authors.initials: TS
authors.lastname: Gibson
authors.forename: John A
authors.initials: JA
authors.lastname: Gaudette
authors.forename: Nathaniel K
authors.initials: NK
authors.lastname: Minami
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Annette E
authors.initials: AE
authors.lastname: Bradbury
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Nolan
authors.forename: J Edward
authors.initials: JE
authors.lastname: Semple
mesh_terms: 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
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007202:Indicators and Reagents; D013917:Thrombin