Conformationally constrained renin inhibitory peptides: .gamma.-lactam-bridged dipeptide isostere as conformational restriction

Thaisrivongs, Suvit; Pals, Donald T.; Turner, Steve R.; Kroll, Lisa T.

doi:10.1021/jm00402a021

Cited by 65 publications

(29 citation statements)

References 2 publications

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“…The peptidomimetic approach was used to obtain generally applicable transition state analogs of the P 1 -P 1 ' Leu-Val sequence in 45 where the hydrolysis of the amide bond takes place, resulting in the norleucine analog 46 (Phe-His) and hydroxymethylene isostere 47 (Leu-Val). Two groups lead by Thaisrivong [53] and de Laszlo [54] independently utilized the Freidinger lactam strategy to constrain the …”

Section: Renin Inhibitors and Angiotensin II Antagonistsmentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

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Section: Renin Inhibitors and Angiotensin II Antagonistsmentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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“…It was hypothesized that the β-hydroxy γ-lactam would provide a better hydrogen bond arrangement for the catalytic Asp residues and at the same time reduce the flexibility, providing a more rigid inhibitor. 35,36 …”

Section: Introductionmentioning

confidence: 99%

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

Öhrngren

Joshi

et al. 2012

J. Med. Chem.

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In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a Ki of 2.1 nM and an EC50 of 0.64 μM. Further optimization by decoration of the P1′ side chain furnished an even more potent HIV-1 protease inhibitor (Ki = 0.8 nM, EC50 = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

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“…First, the macrocycle often preorganizes the molecule into an extended conformation, which can be an ideal conformation for binding to the target enzyme [6]. Second, the macrocycle decreases the conformational entropic penalty for binding to the enzyme when compared to more flexible non-cyclic analogs [14]. Consequently, macrocyclic inhibitors often display enhanced activities.…”

Section: Introductionmentioning

confidence: 99%

Macrocyclic inhibitors for the serine protease plasmin

Xue

Seto

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Macrocyclic inhibitors for the serine protease plasmin were synthesized and evaluated. The inhibitors were constructed starting from a cyclohexanone core. This core was linked to either the C-or N-terminus of a peptide so that the inhibitors were designed to interact with the non-primed or primed binding sites of the protease. Macrocycles were prepared by connecting the side chain of Tyr or Trp, via a short linker, to one end of the peptide. The activities of the macrocyclic inhibitors, while modest, were up to 10-fold more potent than a related non-cyclic analog.

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Conformationally constrained renin inhibitory peptides: .gamma.-lactam-bridged dipeptide isostere as conformational restriction

Cited by 65 publications

References 2 publications

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

Macrocyclic inhibitors for the serine protease plasmin

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