Nichola Smith

The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists.

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.

Iodine catalyzed one pot acetalation-esterification reaction for the preparation of orthogonally protected glycosides

An iodine-catalyzed one-pot tandem acetalation-esterification reaction of thio- and O-glycosides has been developed providing a fast and mild route to orthogonally protected glycosides ready to be used as building blocks in glycosylation reactions.

Synthesis of mucin-type O-glycan probes as aminopropyl glycosides.

Summary The chemical synthesis of a series of mucin-type oligosaccharide fragments 1–7 containing an α-linked aminopropyl spacer ready for glycoarray attachment is reported. A highly convergent and stereoselective strategy that employs two different orthogonal protected galactosamine building blocks was used to access all of the targets. A tandem deprotection sequence, that did not require chromatography-based purification between steps, was employed to globally unmask all protecting groups and all final targets were isolated in good to excellent yields.

Epithelial Na+ channel inhibitors for the treatment of cystic fibrosis

The epithelial Na+ channel (ENaC) is a key regulator of the volume of airway surface liquid (ASL) and is found in the human airway epithelium. In cystic fibrosis (CF), Na+ hyperabsorption through ENaC, in the absence of cystic fibrosis transmembrane conductance regulator mediated anion secretion, results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This review summarizes the published patent applications from 2014 to the end of 2016 that claim approaches to inhibit the function of ENaC for the treatment of CF.