The development of novel agonists and antagonists of APJ as therapeutics for pulmonary arterial hypertension or cancer

The apelinergic system, composed of the GPCR APJ and its endogenous ligand apelin, regulates vasodilation, fluid homeostasis, glucose metabolism and angiogenesis. Dysregulation of the apelinergic system contributes to multiple pathologies, including cancer and hypertension, rending the receptor a potential therapeutic target for intervention in disease. Studies have reported that agonism of APJ decreases blood pressure in hypertensive models whilst antagonism reduces angiogenesis and tumour growth in cancerous mouse and rat models. In Chapter 1, we introduce the apelinergic system as a therapeutic target for hypertension and cancer. In Chapters 2-4, we optimise three series of APJ agonists as potential therapeutics for treatment of hypertension. In Chapter 2, we optimise a previously identified series of agonists, based on a 3H-imidazo[4,5-b]pyridine scaffold. In Chapter 3, we develop a novel series of agonists based on a 1H-imidazole-4-carboxamide scaffold. In Chapter 4, we explore the development of the SAR for a hit compound identified though collaboration with the University of Dundee in their high throughput [35S]GTPγS accumulation screen. As few, genuine small molecule antagonists of APJ are known, we sought to identify a novel antagonist using a combination of different approaches, employing both molecular modelling and general screening. In Chapter 5, we discuss the outcome of an APJ ß-arrestin recruitment screen conducted at the University of Leeds and in Chapter 6, we attempt a process of remodelling a series of APJ agonists, developed by Bristol Myers Squibb, into APJ antagonists via intuitive structural modification and molecular modelling.