New pepstatin analogs: synthesis and pepsin inhibition

McConnell, Rose M.; Frizzell, D; Camp, A.; Evans, Anissa; Jones, Wanda M.; Cagle, Cathy

doi:10.1021/jm00111a054

Cited by 24 publications

(11 citation statements)

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“…The novel chiral aminoalkyl epoxides (Precursor C ) were first reported by Evans and coworkers [40] and have been subsequently used in the preparation of several HIV-1 aspartyl protease inhibitors with hydroxyethyl amine isosteres. In the earlier phase of this project [35, 36, 41] we successfully prepared BOC-protected chiral amino epoxides starting from commercially available corresponding BOC-amino acids. In this paper, we utilized a similar approach for the preparation of the aminoalkyl epoxides with only slight modifications.…”

Section: Resultsmentioning

confidence: 99%

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New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

McConnell

Inapudi²,

Kadasala³

et al. 2012

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The design and synthesis of hydroxyethylamine isosteres as inhibitors of cathepsin D based on SAR data has been accomplished. A library of 96 of these hydroxyethylamine isosteres are described and many have proven to be very potent inhibitors of human cathepsin D activity as measured using a fluorometric assay technique, via peptide substrate Ac-Glu-Glu(Edans)-Lys-Pro-Ile-Cys-Phe-Phe-Arg-Leu-Gly-Lys(Methyl Red)-Glu-NH2. Compounds showing strongest inhibition of cathepsin D activity were those that contain a hydroxyethyl-N’-2- or N’-(4-chlorophenyl)piperazine moiety (IC50 values range from 0.55 to 8.5 nM), with N’-(2-pyrimidyl)piperizine (IC50 values range from 0.5 to 21.6 nM), with N-N’-L-piperazinocolinamide (IC50 values range from 0.001 – 0.25 nM), or N-N’-L-piperazinocolin-N-methylamide (IC50 values range from 0.015 – 7.3 nM) .

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Section: Resultsmentioning

confidence: 99%

“…Elemental analyses demonstrating compound purities of more than 95% were performed by Galbraith Laboratories, Knoxville, TN. Butoxy-carbonyl (BOC)-protected chiral amino epoxides (Precursor C) were prepared as described in our earlier work [35, 36, 41] using a slight modification of a procedure reported by Evans and coworkers [40]. …”

Section: Methodsmentioning

confidence: 99%

New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

McConnell

Inapudi²,

Kadasala³

et al. 2012

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“…The aldehyde was treated with the lithium enolate of ethyl acetate [28–29] at −78 °C according to a modification of the procedure of Steulmann and Klostermeyer [30] to afford two diastereomers 8a and 8b in a 3:2 ratio (as determined by NMR) (Scheme 2). …”

Section: Resultsmentioning

confidence: 99%

Stereoselective synthesis of four possible isomers of streptopyrrolidine

Mohapatra¹,

Thirupathi²,

Das³

et al. 2011

Beilstein J. Org. Chem.

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SummaryThe synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R,5S)-streptopyrrolidine (3) and (4S,5S)-streptopyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reaction with the trimethylsilyl enolate of ethyl acetate and Lewis acid mediated lactamization as the key reactions in ≈42% yield over six steps starting from D-phenylalanine and L-phenylalanine, respectively. The absolute configuration of the natural product was shown to be (4S,5S) by comparing its spectral and analytical data with the reported values.

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“…McConnell et al have described tripeptides ( 2 ) acting as pepsin inhibitors, which contain only the first three N-terminal amino residues of pepstatin A ( 1 ) . Recently, we have reported on comparably simplified analogues ( 3 ), which utilize a vic -amino alcohol in place of the C-terminal statine unit .…”

Section: Chemistrymentioning

confidence: 99%

Simplified Pepstatins: Synthesis and Evaluation of N-Terminally Modified Analogues

Kratzel¹,

Schlichtner²,

Kirchmayer³

et al. 1999

J. Med. Chem.

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The promising strategy of gastric ulcer healing with perorally administered epidermal growth factor (EGF) is so far strongly limited by the pepsinic degradation of this therapeutic polypeptide in the stomach. The incorporation of EGF in a bioadhesive polymer-pepsin inhibitor conjugate used as drug carrier matrix, however, might provide sufficient protection toward pepsinic degradation. The synthesis of appropriate pepsin inhibitors represents a prerequisite for the development of such polymer-inhibitor conjugates. The presented study demonstrates that modifications at the N-terminus of simplified analogues of pepstatin which can be synthesized in a simple and straight way result only in slight variations of the inhibitory activity. These analogues display only 10-fold reduced inhibitory activity, compared to pepstatin A, when bearing a greater N-terminal group like isovaleryl, Boc, or Cbz. Compounds which are substituted at the N-terminus by a shorter N-acyl group like propionyl or cyclopropylcarbonyl show further reduced activity (0.01, compared to pepstatin A). The presence of an amide or a urethane moiety at the N-terminus has no considerable effect on enzyme inhibition. Therefore, the N-terminus of these analogues is able to be modified forming a covalent bond to various bioadhesive polymers via a suitable functionality.

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New pepstatin analogs: synthesis and pepsin inhibition

Cited by 24 publications

References 0 publications

New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

Stereoselective synthesis of four possible isomers of streptopyrrolidine

Simplified Pepstatins: Synthesis and Evaluation of N-Terminally Modified Analogues

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