Hwa-Ok Kim

Recent discovery and development of protein tyrosine phosphatase inhibitors

The protein tyrosine phosphatases (PTPases or PTPs) play an important role in controlling the status of tyrosine phosphorylation and the regulation of cellular function. The ability to selectively inhibit PTPs holds enormous therapeutic potential for the treatment of diseases such as diabetes, cancer and osteoporosis. However, an understanding of the role of many PTPs has yet to be unravelled, with only PTP1B convincingly validated as a therapeutic target. Furthermore, the intricate network of different PTPs extensively involved in signalling events requires high selectivity for the desired PTP target, in order to minimise potential side effects. Most research programmes into PTP inhibitors are still at an early stage and have yet to convert initial leads into compounds with more drug-like properties. Inhibitors have been identified by modification of peptide substrates, from natural product screening and by rational design. This article will give an overview of PTPs, followed by a more detailed description of the development of PTP inhibitors. Patents on PTP inhibitors published between January 1998 and Feb 2002 will be discussed in the context of the available literature.

β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins

There are disclosed β-sheet mimetics and methods relating to the same for imparting or stabilizing the β-sheet structure of a peptide, protein or molecule. In one aspect, β-sheet mimetics are disclosed having utility as protease inhibitors in general and, more specifically, as serine protease inhibitors such as thrombin, elastase and Factor X inhibitors. In one embodiment, the β-sheet mimetic is a thrombin inhibitor.

A merger of rational drug design and combinatorial chemistry: development and application of peptide secondary structure mimetics.

Recent efforts toward the development of peptide secondary structure mimetics at Molecumetics Ltd. for the discoveries of new drug candidates utilizing combinatorial chemistry with solid phase synthesis are described.

Preparation of (R)-2-azidoesters from 2-((p-nitrobenzene)sulfonyl)oxy esters and their use as protected amino acid equivalents for the synthesis of di- and tripeptides containing D-amino acid constituents

Abstract (R)-2-Azidoesters and their derived (R)-2-azido acids are readily prepared from common amino acids by an inversion methodology that employs (S)-2-nosyloxyesters as key intermediates. The (R)-2- azidoesters can be used as protected amino acid equivalents in peptide synthesis. Basic hydrolysis frees the carboxyl group. Triphenylphosphine/water is used to free the amine group. By these reactions a variety of L- D and D-L dipeptides,L-D-L tripeptides,and depsipeptides can be prepared easily in good yields, and without detectable epimerization.

Malic acid: A convenient precursor for the synthesis of peptide secondary structure mimetics

Abstract Syntheses of optically active ether-linked β-lactams and aza-proline analogues via 4-bromo-2-hydroxybutanoic acid esters derived from (S)- or (R)-malic acid are described. From these intermediates peptide secondary structure mimetics can be synthesized.

ACYLATION OF STERICALLY HINDERED SECONDARY AMINES AND ACYL HYDRAZIDES

Abstract The acylation of sterically hindered secondary amines and acyl hydrazides was investigated.

A new chiral alkylation methodology for the synthesis of 2-alkyl-4-ketoacids in high optical purity using 2-triflyloxy esters

Abstract Optical active 2-triflyloxy esters are excellent alkylating agents for β-ketoester enolates. Decarboxylation of the alkylation products gives 2-substituted-4-ketoacid derivatives in high optical purities.

PREPARATION AND SYNTHETIC APPLICATIONS OF STERICALLY HINDERED SECONDARY AMINES

Abstract The preparation of sterically hindered secondary amino esters from the reaction of N-protected α-amino aldehydes and 3-, or 2-oxo esters with α-amino esters by reductive amination is described. The resulting amino esters were converted to the β-lactam or acylated to form N-acyl secondary amides.

Short synthesis of (3S,6S,9S)-2-oxo-3-(N-Boc-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid methyl ester: Tandem cyclization protocol

Abstract A concise enantioselective synthesis of (3S,6S,9S)-2-oxo-3-(N-Boc-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid methyl ester from N-protected glutamic acid is described.

Hydroxyoxazolidines as α-aminoacetaldehyde equivalents: Novel inhibitors of calpain

The synthesis of [1-[(5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl)carbonyl]-2-ethylpropyl]carbamic acid phenylmethyl ester (2; MDL 104,903), a potent inhibitor of calpain, is described. Synthesis of related compounds, which offer insights into the mechanism of action for 2, are also described, as is an O-acetyl prodrug derivative of 2.