Park, Jozef
(2022)
Investigations into novel small molecules as potential treatments for idiopathic pulmonary fibrosis and malaria.
PhD thesis, University of Nottingham.
Abstract
Small molecules provide relatively inexpensive therapeutics for a range of conditions. In contrast with antibody-conjugate treatments and more elaborate treatment options, use of small molecules makes treatment affordable and accessible for all, around the world. This thesis details research into the development of novel small molecule inhibitors of the αV β6 integrin as potential therapeutics for conditions such as idiopathic pulmonary fibrosis (IPF), and also small molecules as therapeutic agents against Plasmodium falciparum for the treatment of malaria.
Small molecule inhibitors of the αV β6 integrin have been identified as attractive targets with therapeutic potential in a range of disease states. A range of diverse, novel αV β6 inhibitors were synthesised from different chemical series, and the structure-activity relationship (SAR) governing the activity of these compounds was explored. The aim of this work was to delineate the selectivity of the compounds for each of the αV integrin receptor isoforms, and determine to what extent SAR information was transferable between the different series. Compounds were synthesised based on the Arginine-Glycine-Aspartic acid (RGD) binding motif which is recognised by the αV integrins. Bioisosteric replacements for the guanidine fragment based on a 1,8-tetrahydronaphthyridine and a 2- (arylamino)-1,4,5,6-tetrahydropyrimidin-5-ol motif were explored. As these cores featured a β-aryl-β-amino acid motif, it was possible to vary the substitution in the aromatic ring in each series to fine-tune and optimise the potency and selectivity profile for the desired αV β6 integrin.
Malaria is a global disease that kills almost half a million people every year. Despite efforts to control the disease, the malaria parasite continues to develop resistance to existing treatments and novel treatments are desperately needed to treat and ultimately to eradicate the disease. The Tres Cantos Antimalarial Sets (TCAMS) published by GSK feature 47 series of drug-like compounds with proven antimalarial activity, providing high quality starting points for antimalarial drug discovery. TCAMS series 38 was selected for further exploration and lead optimisation. Novel analogues based on this initial scaffold were synthesised and these compounds were tested for antimalarial activity in a phenotypic assay.
Chapter 1 provides background detail on idiopathic pulmonary fibrosis, integrin cell biology and highlights the potential of integrin-targeting treatments as therapeutic agents in a range of disease states, including fibrotic diseases and some cancers.
Chapter 2 provides an overview of previous commercial development of integrin inhibitors, in light of the discussion in Chapter 1 regarding the potential of integrin inhibitors as therapeutic agents. Previous work on integrin inhibitors is presented, and existing SAR data are discussed. The targets and aims and objectives of this research project are presented.
Chapter 3 presents the synthesis of novel integrin inhibitors. The biological results of these compounds are also presented and discussed.
Chapter 4 presents a review of literature on malaria, and addresses the desirability of novel treatments for malaria.
Chapter 5 presents work carried out on TCAMS series 38, aiming to synthesise novel analogues in this series with improved drug-like properties as potential new antimalarials.
Chapter 6 contains all experimental details of the work presented in this thesis.
The investigations detailed in this thesis have led to the design, synthesis and biological evaluation of high value novel molecules as potential treatments for fibrotic conditions, malaria, and potentially other disease states. Of the novel compounds detailed in Chapter 3, many were highly potent and showed selectivity for the desired αV β6 integrin isoform, five of these were progressed through in vivo studies in rat and the results of this study will be published in due course. The compounds that were designed, synthesised and evaluated in Chapter 5 allowed for a more in-depth exploration of TCAMS series 38, an under-explored series of compounds with proven antimalarial activity. In the process of synthesising these molecules, methodologies for synthesis relevant to the practicing medicinal chemist have also been developed.
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