Asthma is a chronic respiratory condition that has been estimated to affect more than 350 million people worldwide with a sharp increase over recent years. Despite the availability of multiple medications asthma continues to represent a burden on the lives of many patients. The CCR3 receptor is a seven transmembrane, G-protein-coupled receptor, which belongs to the CC chemokine family. In humans the receptor is expressed on eosinophils, basophils, airway epithelia, airway smooth muscle, dendritic cells, mucosal mast cells and Th2 cells. These cell types are believed to play a key role in the pathophysiology of asthma. Chemokine activation of the CCR3 receptor leads to chemotaxis and activation of cells. The CCR3 receptor is activated by a range of endogenous chemokines, which include eotaxin-1 (CCL11), eotaxin-2 (CCL24) eotaxin-3 (CCL26), MCP-4 (CCL13) and RANTES (CCL5). Levels of these chemokines are raised in allergic diseases such as asthma (atopic and non-atopic), allergic rhinitis and atopic dermatitis. As such antagonists of CCR3 are an attractive target for an oral treatment for asthma and other allergic diseases. In this presentation I will describe the identification and optimisation of a series of phenoxypiperidine based CCR3 antagonists. In the course of this work we encountered many challenges, the first major one of which involved activity at the hERG potassium channel and which we solved by moving from a basic subseries to a zwitterionic one. The clinical results obtained with the first compound will be described. The first identified compound suffered from variable bioavailability related to low solubility and we engaged in a process of scaffold-hopping to identify a subseries with improved physicochemical properties that had reproducibly high bioavailability and long in vivo half-life. Optimisation of the substituents around the molecule leading to the identification of the final clinical candidate will be described. Despite the excellent performance in in vivo models, this last compound and analogues suffered from reproductive toxicity issues that ultimately lead to closure of the programme. The relationship between the physicochemical properties and the observed toxicity will be discussed.

Challenges with zwitterions: Discovery of zwitterionic CCR3 antagonist clinical candidates

2019 Spring National Meeting

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