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Design and Synthesis of Unsymmetrical Peptidyl Urea Inhibitors of Aspartic Peptidases

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Natalie A. Dales,^† Regine S. Bohacek,^‡ Kenneth A. Satyshur,^§ and Daniel H. Rich*^†^§

Department of Chemistry, University of Wisconsin

Madison, 1101 University Avenue, Madison, Wisconsin 53706, ARIAD Pharmaceuticals, 26 Landsdowne Street, Cambridge, Massachusetts 07960, and School of Pharmacy, University of Wisconsin

Madison, 777 Highland Avenue, Madison, Wisconsin 53705

Org. Lett., 2001, 3 (15), pp 2313–2316

DOI: 10.1021/ol0160912

Publication Date (Web): July 4, 2001

Section:

Amino Acids, Peptides, and Proteins

Abstract

The design, synthesis, and enzyme inhibition of a new class of aspartic peptidase inhibitors is described. Unsymmetrical ureas were designed from computer-generated structures. Using mechanism-based and substrate-based design techniques, potent pepsin inhibitors were developed and the binding mode was established. Two X-ray crystal structures of enzyme-bound inhibitors revealed a new binding mode that is closely related to the computer-generated binding mode.

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Citing Articles

View all 15 citing articles

Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.

This article has been cited by 5 ACS Journal articles (5 most recent appear below).

N-Urethane-Protected Amino Alkyl Isothiocyanates: Synthesis, Isolation, Characterization, and Application to the Synthesis of Thioureidopeptides
Vommina V. Sureshbabu, Shankar A. Naik, H. P. Hemantha, N. Narendra, Ushati Das and Tayur N. Guru Row
The Journal of Organic Chemistry2009 74 (15), 5260-5266
- N-Urethane-Protected Amino Alkyl Isothiocyanates: Synthesis, Isolation, Characterization, and Application to the Synthesis of Thioureidopeptides
  Vommina V. Sureshbabu, Shankar A. Naik, H. P. Hemantha, N. Narendra, Ushati Das and Tayur N. Guru Row
  The Journal of Organic Chemistry2009 74 (15), 5260-5266
  Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links
Preparation, Isolation, and Characterization of N^α-Fmoc-peptide Isocyanates: Solution Synthesis of Oligo-α-peptidyl Ureas
Vommina V. Sureshbabu, Basanagoud S. Patil, and Rao Venkataramanarao
The Journal of Organic Chemistry2006 71 (20), 7697-7705
- Preparation, Isolation, and Characterization of N^α-Fmoc-peptide Isocyanates: Solution Synthesis of Oligo-α-peptidyl Ureas
  Vommina V. Sureshbabu, Basanagoud S. Patil, and Rao Venkataramanarao
  The Journal of Organic Chemistry2006 71 (20), 7697-7705
  The Nα-Fmoc-peptide isocyanates 3a−q, 4a−c, and 5a−c were prepared by the Curtius rearrangement of Nα-Fmoc-peptide acid azides in toluene under thermal, microwave, and ultrasonic conditions. All the Nα-Fmoc-oligo-peptide isocyanates made were isolated as ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links
Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases
Ben M. Dunn
Chemical Reviews2002 102 (12), 4431-4458
- Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases
  Ben M. Dunn
  Chemical Reviews2002 102 (12), 4431-4458
  Abstract | Full Text HTML | Hi-Res PDF
Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles
Matthew G. Bursavich and Daniel H. Rich
Journal of Medicinal Chemistry2002 45 (3), 541-558
- Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles
  Matthew G. Bursavich and Daniel H. Rich
  Journal of Medicinal Chemistry2002 45 (3), 541-558
  Abstract | Full Text HTML | Hi-Res PDF
From Peptides to Non-Peptide Peptidomimetics: Design and Synthesis of New Piperidine Inhibitors of Aspartic Peptidases
Matthew G. Bursavich, Chris W. West, and Daniel H. Rich
Organic Letters2001 3 (15), 2317-2320
- From Peptides to Non-Peptide Peptidomimetics: Design and Synthesis of New Piperidine Inhibitors of Aspartic Peptidases
  Matthew G. Bursavich, Chris W. West, and Daniel H. Rich
  Organic Letters2001 3 (15), 2317-2320
  The 3-alkoxy-4-arylpiperidine inhibitors of aspartic peptidases are shown to be a new type of non-peptide peptidomimetic inhibitor. These piperidines can be designed from peptide-derived inhibitors by use of a structure-generating program but only after ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links

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Published In Issue July 26, 2001
Received May 9, 2001

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Letter

Design and Synthesis of Unsymmetrical Peptidyl Urea Inhibitors of Aspartic Peptidases

Abstract

Citing Articles

N-Urethane-Protected Amino Alkyl Isothiocyanates: Synthesis, Isolation, Characterization, and Application to the Synthesis of Thioureidopeptides

N-Urethane-Protected Amino Alkyl Isothiocyanates: Synthesis, Isolation, Characterization, and Application to the Synthesis of Thioureidopeptides

Preparation, Isolation, and Characterization of N^α-Fmoc-peptide Isocyanates: Solution Synthesis of Oligo-α-peptidyl Ureas

Preparation, Isolation, and Characterization of N^α-Fmoc-peptide Isocyanates: Solution Synthesis of Oligo-α-peptidyl Ureas

Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases

Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases

Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles

Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles

From Peptides to Non-Peptide Peptidomimetics: Design and Synthesis of New Piperidine Inhibitors of Aspartic Peptidases