Catherine Howsham

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: quaternary amines.

We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC(50) of 200nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 44μgkg(-1) at 1h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.

Synthesis of a Novel Type of 2,3'-BIMs via Platinum-Catalysed Reaction of Indolylallenes with Indoles

Abstract Optimisation, scope and mechanism of the platinum‐catalysed addition of indoles to indolylallenes is reported here to give 2,3′‐BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3′‐BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt‐catalysed 6‐endo‐trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl‐platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs.

CHAPTER 7:The Discovery of Novel Inhaled ENaC Blockers for the Treatment of Cystic Fibrosis Lung Disease

On a daily basis we can inhale up to 12,000 liters of air, and with this comes a wealth of particles including environmental pollutants, allergens and microbes that impact on the surface epithelium of the lung. The lungs maintain a sterile environment through the utilization of various systems, including phagocytosis of particles by lung resident macrophages, and also through mucociliary (MCC) and cough clearance (CC). An increasing body of data now highlights the degree of lung mucosal hydration as being central to effective MCC and CC, and the salient roles that a number of ion channels can play in the regulation of hydration. This chapter focuses on one of these ion channels – the epithelial sodium channel (ENaC) – and the hypothesis that blocking ENaC in the lung mucosa will result in an enhancement of mucus clearance, thereby reducing the risk of acquiring respiratory infections. A review of the drug discovery approaches to attenuate airway ENaC function, and the status of key experimental compounds in clinical trials, is also provided.