Daniel W. McNeil

Spiro indolinone beta-lactams, inhibitors of poliovirus and rhinovlrus 3C-proteinases

Preparation of the spiro beta-lactam 7 and its evaluation as a poliovirus and human rhinovirus 3C-proteinase inhibitor is described.

Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).

The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.

A simple method for the protection of aryl amines as their t-butylcarbamoyl (Boc) derivatives

It has been found that aryl amines can be directly protected as their Boc derivatives by treatment of the amine with two equivalents of NaHMDS in THF followed by one equivalent of di-t-butyldicarbonate. This procedure works on a wide variety of both electron-rich and electron-deficient aryl amines.

elastase inhibitors containing conformationally restricted lactams as P3-P2 dipeptide replacements

The synthesis of potential human leukocyte elastase (HLE) inhibitors containing conformationally restricted lactams as peptidomimetic replacements at P3-P2 and which contain a trifluoromethyl ketone of valine at P1 are described.

The design of potent hydrazones and disulfides as cathepsin S inhibitors.

The design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo.