Leonie Campbell

Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective Conia-Ene Reaction

A mutually compatible and cooperative combination of copper(I) triflate and bifunctional 9-amino-9-deoxyepicinchona-derived urea compounds for the enantioselective Conia-ene cyclization of alkyne-tethered beta-ketoester substrates is reported. The reaction is efficient, broad in scope, and easy to perform and allows access to chiral methylenecyclopentane products with high enantiocontrol. The transformation illustrates the concept of combining inactive precatalysts with inactive transition-metal-ion complexes in situ to reversibly create a catalytically active combination of the two.

Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.

The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.

Matched triplicate design sets in the optimisation of glucokinase activators – maximising medicinal chemistry information content

Successful lead optimisation requires the identification of the best compound within the chemical space explored during an optimisation campaign. This can be a costly and inefficient process leading to the synthesis of many sub-optimal compounds. In this paper, a method for carrying out this exercise more effectively is outlined. This relies on the generation of robust datasets on which to build predictive models in a paradigm termed “matched triplicate design sets”. The practical implementation of this approach is exemplified in the optimisation of a new series of glucokinase activators.

Optimising pharmacokinetics of glucokinase activators with matched triplicate design sets – the discovery of AZD3651 and AZD9485

The matched triplicate approach to lead optimisation offers a means of generating more robust quantitative structure activity relationship data and this rigour leads to better quality decision making and greater ability to predict optimal compounds within a series. One of the ultimate aims of this approach is to use the data generated to build more accurate predictive models to identify the best compounds within the exemplified chemical space in an efficient manner. This paper describes the continued application of this approach to the optimisation of a series of glucokinase activators. This second phase focussed primarily on the rational solution to plasma instability observed with the previous compounds and, hence, achieved acceptable oral exposure in the series. The campaign was completed by using the predictive power of Free-Wilson analysis based on the matched triplicate datasets to enable a focussed, matrix based endgame culminating in the identification of two development candidates, AZD3651 and AZD9485.

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353

Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.

Manganese‐Catalyzed Hydrofunctionalization of Alkenes

The manganese-catalyzed hydrosilylation and hydroboration of alkenes has been developed using a single manganese(II) precatalyst and reaction protocol. Both reactions proceed with excellent control of regioselectivity and in high yields across a variety of sterically and electronically differentiated substrates (25 examples). Alkoxide activation, using NaOt Bu, was key to precatalyst activation and reactivity. Catalysis was achieved across various functional groups and on gram-scale for both the developed methodologies with catalysts loadings as low as 0.5 mol %.