Craig Jamieson

Evaluation of alternative solvents in common amide coupling reactions: replacement of dichloromethane and N,N-dimethylformamide

formation is the single most common synthetic transformation used within medicinal chemistry. Indeed, several studies have demonstrated the prevalence of this particular transformation within the pharmaceutical sector: MacDonald’s analysis of the GlaxoSmithKline (GSK) Respiratory Centre of Excellence for Drug Discovery revealed that 17% of all reaction types conducted in array (focused library) format were to prepare amide or sulfonamide moieties. 3 Similarly, Roughley’s analysis of the most common reactions used within synthetic medicinal chemistry research across three of the largest pharmaceutical companies (GSK, AstraZeneca, and Pfizer) indicated that N-acylation to prepare amides ranked 1st for frequency of use, accounting for 16% of all reactions performed and with the amide linkage present in 54% of the compound set analysed. 4

A novel series of positive modulators of the AMPA receptor: discovery and structure based hit-to-lead studies.

Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

Organobase-catalyzed amidation of esters with amino alcohols.

A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification of the catalytic process are described, furnishing products in 40-100% isolated yield.

Structure based evolution of a novel series of positive modulators of the AMPA receptor

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.

Positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

L-glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a fundamental role in the control of motor function, cognition and mood. The physiological effects of glutamate are mediated through two functionally distinct receptor families. While activation of metabotropic (G-protein coupled) glutamate receptors results in modulation of neuronal excitability and transmission, the ionotropic glutamate receptors (ligand-gated ion channels) are responsible for mediating the fast synaptic response to extracellular glutamate.

Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data.

A novel series of positive modulators of the AMPA receptor: structure-based lead optimization.

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

Development of a solvent selection guide for aldehyde-based direct reductive amination processes

A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic processes.

Replacement of dichloromethane within chromatographic purification: a guide to alternative solvents†‡

Replacement of dichloromethane as the bulk medium within chromatographic purification has been evaluated with a broad range of molecules containing functionality common within Medicinal Chemistry programmes. Analysis of the data set has generated a set of general guidelines to assist in the selection of alternative solvents for CH2Cl2 as the bulk media in these ubiquitously employed processes.

Cathepsin K inhibitors, 2000 – 2004

Cathepsin K is one of eleven cysteine proteases from the papain superfamily known to be expressed in the human genome. Its selective and abundant expression in osteoclasts and critical role in the degradative phase of bone remodelling suggests that selective inhibition of cathepsin K may provide an effective therapy for the treatment of osteoporosis. This hypothesis has generated considerable interest over the past decade in the development of selective cathepsin K inhibitors. Around 190 cathepsin K-related patent applications have been filed since its discovery in rabbit osteoclasts a decade ago; half of which were published in the last two years, indicating the rapidly increasing level of activity in the field. Small-molecule cathepsin K inhibitors have been reported to show efficacy in animal models of osteoporosis. Most recently, the disclosure from Novartis of the successful completion of Phase IIa trials is likely to attract even greater attention to the target. In addition to a role in bone remodelling, evidence supporting the involvement of cathepsin K in spontaneous rupture of atherosclerotic plaque, leading to arterial thrombosis and potentially fatal myocardial infarction, has also been reported recently. This review is focused on recent advances in the development of specific cathepsin K inhibitors, based on the patent literature from January 2000 to June 2004. Given that rapid advances in this period are directly attributable to the availability of crystallographic data, biostructural information related to key enzyme/inhibitor interactions is also briefly summarised.