Exploratory solid-phase synthesis of factor Xa inhibitors: discovery and application of p3-heterocyclic amides as novel types of non-basic arginine surrogates.
A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported.
Ho
J Z
JZ
Department of Medicinal Chemistry, Corvas International, Inc. San Diego, California 92121, USA.
Levy
O E
OE
Gibson
T S
TS
Nguyen
K
K
Semple
J E
JE
D000577:Amides / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds; D015842:Serine Proteinase Inhibitors; D001120:Arginine