Late-Stage Functionalization by Chan-Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors.

A late-stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper-catalysed diversification of a boronate ester by amination (Chan-Lam reaction) that can be carried out on a complex ß-aryl-ß-amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high-throughput-array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug-like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire.

Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids.

A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.

Active Search for Computer-aided Drug Design.

We consider lead discovery as active search in a space of labelled graphs. In particular, we extend our recent data-driven adaptive Markov chain approach, and evaluate it on a focused drug design problem, where we search for an antagonist of an αv integrin, the target protein that belongs to a group of Arg-Gly-Asp integrin receptors. This group of integrin receptors is thought to play a key role in idiopathic pulmonary fibrosis, a chronic lung disease of significant pharmaceutical interest. As an in silico proxy of the binding affinity, we use a molecular docking score to an experimentally determined αvß6 protein structure. The search is driven by a probabilistic surrogate of the activity of all molecules from that space. As the process evolves and the algorithm observes the activity scores of the previously designed molecules, the hypothesis of the activity is refined. The algorithm is guaranteed to converge in probability to the best hypothesis from an a priori specified hypothesis space. In our empirical evaluations, the approach achieves a large structural variety of designed molecular structures for which the docking score is better than the desired threshold. Some novel molecules, suggested to be active by the surrogate model, provoke a significant interest from the perspective of medicinal chemistry and warrant prioritization for synthesis. Moreover, the approach discovered 19 out of the 24 active compounds which are known to be active from previous biological assays.

Unusual Undergraduate Training in Medicinal Chemistry in Collaboration between Academia and Industry.

Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design-synthesize-test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds. Considerable emphasis is placed on standard design properties used within industry. The modules are popular with the students and usually oversubscribed. An unexpected benefit has been the opportunities that have emerged with research and commercial potential. Graduate and postgraduate training of medicinal chemists at GSK is also briefly described.

Passing on the medicinal chemistry baton: training undergraduates to be industry-ready through research projects between the University of Nottingham and GlaxoSmithKline.

In this article we describe a radically different industry-academia collaboration between the School of Chemistry, University of Nottingham, and GlaxoSmithKline (GSK), aiming to train students in research and give them an insight into medicinal chemistry as practiced in industry. The project concerns the discovery of potent and selective αvß6 integrin antagonists to treat idiopathic pulmonary fibrosis; the synthetic chemistry is performed by a group of ten final-year undergraduates and the biological and physicochemical screening data are generated by GSK. The project planning, organisation and operation are discussed, together with some of the challenges and rewards of working with undergraduates.

Relative binding affinities of integrin antagonists by equilibrium dialysis and liquid chromatography-mass spectrometry.

The integrin αvß6 is a potential target for treatment of idiopathic pulmonary fibrosis (IPF). Equilibrium dialysis (ED) was investigated for its ability to report ligand binding in an αvß6 inhibitor screening assay. As a preliminary experiment, an established peptidomimetic inhibitor of the integrin was dialyzed against αvß6, and the fraction bound (f b) and percentage saturation determined by liquid chromatography-mass spectrometry (LC-MS) analysis. Quantitation of the inhibitor in the two chambers of the ED cartridge revealed an uneven distribution in the presence of αvß6, corresponding to near saturation binding to the protein (93 ± 3%), while the control (without integrin) showed an equal partitioning of the inhibitor on either side of the dialysis membrane. A competitive ED assay with a 12 component mixture of antagonists was conducted, and the results compared with an established cell adhesion assay for quantifying αvß6 inhibition of individual antagonists. Compounds clustered into three groupings: those with pIC 50 values between ca. 5.0 and 5.5, which possessed ED f b values indistinguishable from the controls, those with pIC 50s of 6.5 ± 0.2, which exhibited detectable integrin binding (f b 13-25%) in the ED assay, and a single compound of pIC 50 7.2 possessing an f b value of 38%. A good correlation between ED-derived f b and pIC 50 was observed despite the two assays utilizing quite different outputs. These results demonstrate that ED with LC-MS detection shows promise as a rapid αvß6 integrin antagonist screening assay for mixtures of putative ligands.

Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Antagonism of αvß6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvß3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvß6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvß3, αvß5, αvß6, and αvß8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvß3 and αvß5.