Fibrotic diseases can be attributed to approximately 45% of deaths within western developed countries. This category of disease can affect nearly every tissue in the body, predominantly liver, kidney, and lung. The severity of fibrotic diseases is widely recognised but currently there is no accepted effective disease modifying treatment. There have been a number of potential drug targets identified in recent years, including the enzyme autotaxin (ATX) and the RGD integrins, which are known to play a key role in the pathogenesis. In collaboration with GlaxoSmithKline, the projects detailed in this report were aimed to develop small molecule inhibitors with drug like physicochemical properties for fibrosis drug discovery.Chapter 1 focusses on the secreted enzyme ATX, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognised therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, Chapter 1 details the structure-activity relationship (SAR) exploration of a previously reported small molecule ATX inhibitor through the design, synthesis, and biological evaluation of aseries of analogues.Furthermore, using enzyme kinetics studies it is shown that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX the discrete binding mode was confirmed. This work has provided valuable insight into the binding of this chemotype, which could aid the design of novel ATX inhibitors with non-lipid-like scaffolds.Chapter 2 describes a lead-optimisation project targeting the RGD subfamily of the integrin receptors. The RGD integrins are recognised therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence of the natural ligands (arginine-glycine-aspartic acid); however, the RGD-mimetic antagonists for one particular RGD integrin (αIIbβ3) have been shown to cause partial agonism, leading to the opposite pharmacological effect.The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrintherapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic.The work detailed herein aimed to build on this emerging area, with the design, synthesis, and biological evaluation of novel small molecule inhibitors targeting the αvβ3 integrin. These compounds are shown to be accessed via synthetically divergent routes, allowing for the quick exploration of adiverse set of potential lead compounds. Initial efforts led to the identification offour promising lead-like inhibitors with pIC50 values ranging from 4.1-5.5 for the target integrin αvβ3. Unfortunately, the initial hit compound, that the subsequent compound design stemmed from, was later determined to be a false positive, and as a result work on the project ceased. Thus, Chapter 2 details a project that was misled due to false positive assay results.
|Date of Award||17 Mar 2017|
- University Of Strathclyde
|Sponsors||EPSRC (Engineering and Physical Sciences Research Council)|
|Supervisor||Allan Watson (Supervisor) & Craig Jamieson (Supervisor)|