Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists

William J. Hoekstra; Mary Pat Beavers; Patricia Andrade-Gordon; Mary F. Evangelista; Patricia M. Keane; Jeffery B. Press; Karen A. Tomko; Francis Fan; Marek Kloczewiak; Kevin H Mayo; Kathleen A. Durkin; Dennis C. Liotta

doi:10.1021/jm00010a002

Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists

William J. Hoekstra
, Mary Pat Beavers
, Patricia Andrade-Gordon
, Mary F. Evangelista
, Patricia M. Keane
, Jeffery B. Press
, Karen A. Tomko
, Francis Fan
, Marek Kloczewiak
, Kevin H Mayo
, Kathleen A. Durkin
, Dennis C. Liotta

Structural Biology and Biophysics (TMED)

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the γ-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (26), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC₅₀ = 0.009 μM), as well as thrombin- or collagen-induced platelet aggregation (IC₅₀ = 0.76, 0.14 μM). Since the 400-411 sequence is required for γ-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-á-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.

Original language	English (US)
Pages (from-to)	1582-1592
Number of pages	11
Journal	Journal of medicinal chemistry
Volume	38
Issue number	10
DOIs	https://doi.org/10.1021/jm00010a002
State	Published - May 1 1995

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@article{340fbedbe2b744d4be0a5b6863e0bb2e,

title = "Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists",

abstract = "Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the γ-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (26), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 μM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 μM). Since the 400-411 sequence is required for γ-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-{\'a}-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.",

author = "Hoekstra, \{William J.\} and Beavers, \{Mary Pat\} and Patricia Andrade-Gordon and Evangelista, \{Mary F.\} and Keane, \{Patricia M.\} and Press, \{Jeffery B.\} and Tomko, \{Karen A.\} and Francis Fan and Marek Kloczewiak and Mayo, \{Kevin H\} and Durkin, \{Kathleen A.\} and Liotta, \{Dennis C.\}",

year = "1995",

month = may,

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doi = "10.1021/jm00010a002",

language = "English (US)",

volume = "38",

pages = "1582--1592",

journal = "Journal of medicinal chemistry",

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TY - JOUR

T1 - Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists

AU - Hoekstra, William J.

AU - Beavers, Mary Pat

AU - Andrade-Gordon, Patricia

AU - Evangelista, Mary F.

AU - Keane, Patricia M.

AU - Press, Jeffery B.

AU - Tomko, Karen A.

AU - Fan, Francis

AU - Kloczewiak, Marek

AU - Mayo, Kevin H

AU - Durkin, Kathleen A.

AU - Liotta, Dennis C.

PY - 1995/5/1

Y1 - 1995/5/1

N2 - Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the γ-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (26), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 μM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 μM). Since the 400-411 sequence is required for γ-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-á-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.

AB - Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the γ-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (26), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 μM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 μM). Since the 400-411 sequence is required for γ-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-á-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.

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AN - SCOPUS:0029031716

SN - 0022-2623

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SP - 1582

EP - 1592

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 10

ER -

Design and Evaluation of Nonpeptide Fibrinogen γ-Chain Based GPIIb/IIIa Antagonists

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