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Exploiting the Molecular Template of Angiotensinogen in the Discovery and Design of Peptidyl, Pseudopeptidyl and Peptidemimetic Inhibitors of Human Renin: A Structure-Activity Perspective

  • Tomi K. Sawyer
  • Jackson B. Hester
  • Heinrich J. Schostarez
  • S. Thaisrivongs
  • Gordon L. Bundy
  • Li Liu
  • V. Susan Bradford
  • Anne E. De Vaux
  • Douglas J. Staples
  • Linda L. Maggiora
  • Ruth E. TenBrink
  • John H. Kinner
  • Clark W. Smith
  • Donald T. Pals
  • Sally J. Couch
  • Jessica S. Hinzmann
  • Roger A. Poorman
  • Howard M. Einspahr
  • Barry C. Finzel
  • Keith D. Watenpaugh
  • Boryeu Mao
  • Dennis E. Epps
  • Ferenc J. Kezdy
  • Robert L. Heinrikson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 306)

Abstract

The design of potent and pharmacologically effective, substrate-related inhibitors of renin has been the subject of intensive pharmaceutical discovery research for about one decade. Milestone achievements in synthetic tailoring of fragment analogs of angiotensinogen (ANG; Figure 1) have been documented in terms of identifying renin inhibitors of subnanomolar potency, sustained in vivo hypotensive activity, stability towards proteolytic degradation, and, more recently, oral bioavailability and decreased systemic clearance.1 By chemical modification of ANG-based derivatives, structure-activity analysis, and computer-assisted molecular modeling of peptidyl, pseudopeptidyl and peptidemimetic inhibitors using 3-D structural models of human renin, there currently exists a rather sophisticated wealth of information of relevance to the “rational” design of prototypic renin-targeted cardiovascular therapeutic agents. Such efforts have bridged biochemistry, medicinal chemistry, computational and biophysical chemistry, and in vivo pharmacology including, in a few cases, clinical evaluation in humans.

Keywords

Aspartic Proteinase Renin Inhibitor Aspartyl Protease Human Renin Human Immunodeficiency Virus Protease Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Tomi K. Sawyer
    • 1
  • Jackson B. Hester
    • 1
  • Heinrich J. Schostarez
    • 1
  • S. Thaisrivongs
    • 1
  • Gordon L. Bundy
    • 1
  • Li Liu
    • 1
  • V. Susan Bradford
    • 1
  • Anne E. De Vaux
    • 1
  • Douglas J. Staples
    • 1
  • Linda L. Maggiora
    • 1
  • Ruth E. TenBrink
    • 1
  • John H. Kinner
    • 1
  • Clark W. Smith
    • 1
  • Donald T. Pals
    • 1
  • Sally J. Couch
    • 1
  • Jessica S. Hinzmann
    • 1
  • Roger A. Poorman
    • 1
  • Howard M. Einspahr
    • 1
  • Barry C. Finzel
    • 1
  • Keith D. Watenpaugh
    • 1
  • Boryeu Mao
    • 1
  • Dennis E. Epps
    • 1
  • Ferenc J. Kezdy
    • 1
  • Robert L. Heinrikson
    • 1
  1. 1.Upjohn LaboratoriesThe Upjohn CompanyKalamazooUSA

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