Stephen Peter East

Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ

3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.

DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: synthesis and antibacterial activity.

The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.

Arylsulfonamide CB2 receptor agonists: SAR and optimization of CB2 selectivity.

A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: Modification of the metal binding group

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.

mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455

Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinsons disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC50s < 500 nM.

Chapter 20:Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE)

The discovery of new antibacterials to combat the emergence of resistant organisms is of global importance. One strategy to reduce the development of resistance in new drugs is to identify a single pharmacophore that has the ability to target more than one essential bacterial enzyme. This opportunity has already been realised with certain drugs from the quinolone/fluoroquinolone class of antibiotics, and these drugs act via the GyrA and ParC subunits on the bacterial type II topoisomerases DNA gyrase and topoisomerase IV. This class of enzymes also presents a second opportunity for single pharmacophore multi-target inhibitors as they contain similarly conserved binding sites on the GyrB and ParE subunits which are responsible for the hydrolysis of ATP, a critical step in these enzymes’ function. Competitive inhibitors of ATP have been shown to inhibit both GyrB and ParE and to reduce spontaneous resistance in vitro which is indicative of dual-target action. This chapter will focus on one chemical class of dual-targeting DNA gyrase and topoisomerase IV inhibitors, the ethyl ureas, and will present some of the preclinical data supporting their mechanism of action as a novel series of antibacterials.