Application of bioisosteres to modulate molecular properties in medicinal chemistry

Previously held under moratorium in Chemistry department (GSK) from 14th June 2017 until 23rd November 2022.The confidentiality statement on each page of this thesis DOES NOT applyThis research describes the use of bioisosteres within two medicinal chemistry programmes. Firstly, a bicyclo[1.1.1]pentane (BCP) was investigated as a phenyl group replacement in an attempt to improve the physicochemical profiles of two Lp-PLA2 inhibitors. Installation of the BCP unit was accomplished through a challenging 10-step synthesis in reasonable yields. The physicochemical profiles of both inhibitors were enhanced with high potency maintained when one BCP inhibitor was compared to its parent. With the enhancement in physicochemical profiles the application of the BCP unit to alternative systems was desired. To this end, the synthetic route to the BCP was investigated in order to allow access to a variety of functionality across the BCP moiety. Electron deficient aromatic systems proved to be the most suitable analogues to the route investigated with significant challenges encountered on alternative templates. Additionally, isolation of the mono-chlorinated BCP stimulated interest in potential cross-coupling reactions to generate novel BCP systems. An extensive investigation provided no desired cross-coupled product with ring opening of the BCP providing a considerable challenge. Bioisosteres were also investigated in the context of BET inhibition. Utilising an ester as a bioisosteric amide group allowed investigation of a soft-drug approach to BET inhibitors. Replacement of a methyl amide with an ester allowed retention of potency at the target with the introduction of a metabolically labile group to facilitate site selective inhibition. The lability of the ester group was investigated in a human whole blood assay to investigate the half-lives of the compounds, in which it was shown that the ester functionality was unstable. This provided good evidence to support the soft-drug approach in BET inhibition. Further elaboration of the initial hit led to an unforeseen reduction in potency which was rationalised as a conformational bias against the optimum geometry for binding.This research describes the use of bioisosteres within two medicinal chemistry programmes. Firstly, a bicyclo[1.1.1]pentane (BCP) was investigated as a phenyl group replacement in an attempt to improve the physicochemical profiles of two Lp-PLA2 inhibitors. Installation of the BCP unit was accomplished through a challenging 10-step synthesis in reasonable yields. The physicochemical profiles of both inhibitors were enhanced with high potency maintained when one BCP inhibitor was compared to its parent. With the enhancement in physicochemical profiles the application of the BCP unit to alternative systems was desired. To this end, the synthetic route to the BCP was investigated in order to allow access to a variety of functionality across the BCP moiety. Electron deficient aromatic systems proved to be the most suitable analogues to the route investigated with significant challenges encountered on alternative templates. Additionally, isolation of the mono-chlorinated BCP stimulated interest in potential cross-coupling reactions to generate novel BCP systems. An extensive investigation provided no desired cross-coupled product with ring opening of the BCP providing a considerable challenge. Bioisosteres were also investigated in the context of BET inhibition. Utilising an ester as a bioisosteric amide group allowed investigation of a soft-drug approach to BET inhibitors. Replacement of a methyl amide with an ester allowed retention of potency at the target with the introduction of a metabolically labile group to facilitate site selective inhibition. The lability of the ester group was investigated in a human whole blood assay to investigate the half-lives of the compounds, in which it was shown that the ester functionality was unstable. This provided good evidence to support the soft-drug approach in BET inhibition. Further elaboration of the initial hit led to an unforeseen reduction in potency which was rationalised as a conformational bias against the optimum geometry for binding