Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based peptide mimetics by anchoring to a secondary amide

H C Zhang; D F McComsey; K B White; M F Addo; P Andrade-Gordon; C K Derian; D Oksenberg; B E Maryanoff

doi:10.1016/s0960-894x(01)00378-x

Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based peptide mimetics by anchoring to a secondary amide

Bioorg Med Chem Lett. 2001 Aug 20;11(16):2105-9. doi: 10.1016/s0960-894x(01)00378-x.

Authors

H C Zhang¹, D F McComsey, K B White, M F Addo, P Andrade-Gordon, C K Derian, D Oksenberg, B E Maryanoff

Affiliation

¹ Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA. [email protected]

PMID: 11514149
DOI: 10.1016/s0960-894x(01)00378-x

Abstract

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.

MeSH terms

Amides / chemistry
Fibrinolytic Agents / chemical synthesis
Fibrinolytic Agents / chemistry
Fibrinolytic Agents / pharmacology
Indazoles / chemical synthesis*
Indazoles / chemistry
Indazoles / pharmacology
Indoles / chemistry
Molecular Mimicry
Receptors, Thrombin / antagonists & inhibitors*
Urea / analogs & derivatives
Urea / chemical synthesis*
Urea / chemistry
Urea / pharmacology

Substances

Amides
Fibrinolytic Agents
Indazoles
Indoles
RWJ 58259
RWJ-53052
RWJ-56110
Receptors, Thrombin
indole
Urea