Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based peptide mimetics by anchoring to a secondary amide.
A novel, 10-step, solid-phase method, based on a secondary amide linker, was developed to construct a diverse library of indole-based SFLLR peptide mimetics as thrombin receptor (protease-activated receptor 1, PAR-1) antagonists. The key steps include stepwise reductive alkylation, urea formation, and Mannich reaction. Screening of the library led to a quick development of the SAR and the significant improvement of PAR-1 activity.
Zhang
H C
HC
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA. hzhang@prius.jnj.com
McComsey
D F
DF
White
K B
KB
Addo
M F
MF
Andrade-Gordon
P
P
Derian
C K
CK
Oksenberg
D
D
Maryanoff
B E
BE
D000577:Amides / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry; D018716:Molecular Mimicry; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D005343:Fibrinolytic Agents; D007191:Indazoles; D007211:Indoles; C424723:RWJ 58259; C435605:RWJ-53052; C435606:RWJ-56110; D018179:Receptors, Thrombin; C030374:indole; D014508:Urea