Thomas Elebring

The orphan receptor GPR55 is a novel cannabinoid receptor

The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes.

Asymmetric synthesis of esomeprazole

Abstract A highly efficient synthesis of esomeprazole—the ( S )-enantiomer of omeprazole—via asymmetric oxidation of prochiral sulphide 1 is described. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide (CHP) in the presence of ( S , S )-diethyl tartrate [( S , S )-DET]. The enantioselectivity was provided by preparing the titanium complex in the presence of 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of 1 in the presence of an amine. An enantioselectivity of >94% ee was obtained using this method.

Identification and characterisation of a novel splice variant of the human CB1 receptor

Cannabinoid ligands are implicated in many physiological processes and to date two receptors have been identified. However, a growing body of evidence exists that suggests the presence of additional receptors. Whilst cloning the previously described hCB1a, we have identified a novel variant that we call hCB1b. Characterising these two splice variants demonstrates that they have a unique pharmacological profile and that their RNAs are expressed at low levels in a variety of tissues.

(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action.

Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABAB receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABAB receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABAB receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABAB receptor antagonist and absent in GABAB−/− mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABAB receptors and may offer a potential new approach to treatment of GERD.

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.

Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules

A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.

Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors

We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.

What is the most important approach in current drug discovery: doing the right things or doing things right?

Doing the right things or doing things right: what is the most important focus for current drug discovery to secure delivery of new drugs of sustainable value to patients, healthcare professionals and healthcare providers? Some of the challenges faced today in drug discovery are addressed here: the relationship between R&D speed, cost and quality; how selection of performance metrics can affect the quality of the R&D output; the importance of leadership and management; how process orientation can affect, for example, creativity and innovation; the importance of selecting the right pharmacologic target and the right chemical lead; and why the use of drug-target kinetic and thermodynamic data to drive lead selection and lead optimization could increase success rates.

Effects of (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice

The effects of the novel GABA analogue (2R)‐(3‐amino‐2‐fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABAA/GABAB selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55±8% after intragastric administration of AFPSiA at 14 μmol kg−1 and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37±6 and 16±9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 μmol kg−1. The oral availability of AFPSiA was 52±17 and 71±4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)‐(3‐amino‐2‐fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABAB (Ki=47±4.4 nM) compared to GABAA (Ki=430±46 nM) binding sites. The compound was a full agonist at human recombinant GABAB(1a,2) receptors (EC50=130±10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABAA (Ki=37±3.1 nM) vs GABAB (Ki=6800±280 nM) receptors. In the mouse, high doses (1–8 mmol kg−1) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg−1). This effect was unaffected by the selective GABAB receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg−1) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg−1. It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABAA receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.

Regioselective Synthesis of Highly Aryl‐Substituted Pyrrole Carboxylates as Useful Medicinal Chemistry Leads

Abstract The regioselective syntheses of two pharmaceutically relevant pyrrole scaffolds are described. A synthetic route for the preparation of differentially substituted pyrrole‐3,4‐dicarboxylates is presented and exemplified. This route circumvents some of the problems and limitations associated with previous butynedioic diester condensations and 1,3‐dipolar cycloaddition reactions. A route to the related 4,5‐diarylpyrrole‐2‐carboxylic acid scaffold is also presented. Both routes allow for the regiocontrolled preparation of highly substituted pyrrole pharmacophore cores.