Craig Johnstone

Development of Dirhodium(II)‐Catalyzed Generation and Enantioselective 1,3‐Dipolar Cycloaddition of Carbonyl Ylides

Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddition of 2-diazo-3,6-diketoester 2 with the use of dirhodium tetrakiscarboxylate and tetrakisbinaphtholphosphate catalysts to give the cycloadducts 3 in good yields and up to 90% ee is described.

Catalytic Enantioselective Tandem Carbonyl Ylide Formation-Cycloaddition

Abstract Catalytic enantioselective tandem carbonyl ylide formation-cycloaddition of α-diazo-β-ketoesters 1 (R = alkyl, n = 1,2) using 1 mol% [Rh2(S-DOSP)4] 2 in hexane at room temperature to give the cycloadducts 3 in good yields and up to 53% ee are described.

Creativity, innovation and lean sigma: a controversial combination?

The application of lean sigma is gaining momentum in drug discovery and development but it remains controversial because of perceptions that process improvement will suppress much-needed creativity and innovation. We review the conditions required to support creativity and innovation and the principles and benefits of lean sigma in a drug discovery environment. We conclude that it is desirable to create a unified climate that encourages and enables both innovation and continuous improvement and that this is possible if three key tensions are handled carefully and with due respect to the needs of research. These three potential traps occur in the interpretation of standardization, the role of variation and the choice of how to use liberated capacity.

Making medicinal chemistry more effective—application of Lean Sigma to improve processes, speed and quality

The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.

Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092

Small molecule activators of the glucokinase enzyme have the potential to deliver a level of glycaemic control that is superior to current oral agents and hence have great promise as new therapies for Type 2 Diabetes. As such, attempts to discover glucokinase activators suitable for clinical development have been the focus of many major pharmaceutical research programmes. Here we show how property-based matrix optimisation has been used to improve the multi-parameter technical profile of the AstraZeneca series of glucokinase activators culminating in the discovery of the development candidate AZD1092.

A stable catalyst of the Pauson–Khand annelation

A practical catalytic-in-cobalt version of the PKA is clearly a desirable objective and there has been much research towards this goal in recent years. Systems developed to date, however, require either the use of high temperatures and high carbon monoxide pressures and/or the use of the sensitive cobalt catalyst, octacarbonyldicobablt(0). We report here a detailed account of PKA results obtained using the more robust cobalt compound, heptacarbonyl(triphenylphosphine)dicobalt(0), 1, which indicate that 1 is an attractive alternative to octacarbonyldicobalt(0) as a catalyst of the PKA.

Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life.

The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.

Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656

Glucokinase plays a central role in glucose homeostasis and small molecule activators of the glucokinase enzyme have been the subject of significant pharmaceutical research in the quest for agents capable of delivering improved glycaemic control. Here we describe our medicinal chemistry campaign to improve on our previously described development candidate in this area, AZD1092, focussed on removal of Ames liability and improved permeability characteristics. This work culminated in the superior compound AZD1656 which has progressed to phase 2 clinical trials.

The application of polymer-bound carbonylcobalt(0) species in linker chemistry and catalysis

Carbonylcobalt(0) species have been used as linkers between alkynes and a polymer support for the first time. The alkynes may be loaded indirectly onto a phosphine functionalised polymer via their hexacarbonyldicobalt(0) complex, or directly onto a cobalt coated polymer. The alkynes have been released either as alkynes, thus providing a traceless method of immobilising alkynes, or by reaction with an alkene to generate a cyclopentenone via the Pauson-Khand reaction. The cobalt coated polymers produced during this study were shown to catalyse the Pauson-Khand reaction.

Medicinal chemistry matters – a call for discipline in our discipline

Medicinal chemistry makes a vital contribution to small molecule drug discovery, and the quality of it contributes directly to research effectiveness as well as to downstream costs, speed and survival in development. In recent years, the discipline of medicinal chemistry has evolved and witnessed many noteworthy contributions that propose and offer potential improvements to medicinal chemistry practice; however, the impact of these ideas is limited by their acceptance and deployment into every-day activity and, as a result, the quality of medicinal chemistry remains variable. For the good of the industry and the medicinal chemistry discipline, there is a need to move from retrospective learning to prospective control of medicinal chemistry practice to improve cost effectiveness, probability of success and survival rates.