Sverker von Unge

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.

(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.

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.

Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties

A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.

Stability of arylglycerols during alkaline cooking

According to degradation studies (Nimz 1966; Lundquist and Lundgren 1972) and NMR studies (Lundquist 1992; Kilpeläinen et al. 1994) a few units of type 2 are also present in non-treated lignin. Arylglycerols wguaiacylglycerol (4) (Löwendahl et al. 1978; Niemelä and Sjöström 1986; Niemelä 1988a,b) and syringylglycerol (5) (Niemelä and Sjöström 1986; van der Klashorst and Strauss 1987)xhave been detected in liquors from alkaline pulping. Guaiacylglycerol (4) has also been shown to form on soda cooking of isolated spruce lignin (Lundquist 1973). The liberation of arylglycerols requires the cleavage of the aryl ether bond attaching the arylglycerol to the lignin (Figure 1). The formation of 2 from 1 represents one type of cleavage reaction that can lead to the liberation of 3 from 2. Other possible aryl ether cleavage reactions are shown in Figure 2. This figure summarizes results from soda cooking experiments with a model compound (6) representative of phenolic guaiacylglycerol b-guaiacyl ethers. The formation of an enol ether (8) predominates (Gierer and Norén 1962a); the enol ether is comparatively stable but it undergoes cleavage to some extent (Dimmel and Bovee 1993) (Figure 2, reaction route A). Initial b-ether cleavage also occurs (Jansson and Fullerton 1987), in particular in the presence of certain carbohydrates or ‘‘carbohydraterelated’’ compounds (Jansson and Fullerton 1987; see also Fullerton and Wilkins 1985) (Figure 2, reaction route B). An alternative mechanism involving quinone methide radical anions has been proposed as an explanation of the effects of carbohydrates (Smith and Dimmel 1988). Degradation via homolysis of an intermediate quinone methide (analogous to 7 in Figure 2) is the predominating reaction of syringylglycerol b-syringyl ethers (Li et al. 2000). Proof of the occurrence of homolytic cleavage of 7 (Figure 2, reaction route C) has not been presented in the case of guaiacylglycerol b-guaiacyl ethers. However, the low or moderate increase in the yield of guaiacol observed when certain carbohydrates or ‘‘carbohydraterelated’’ compounds are present in the cooking mixtures (Jansson and Fullerton 1987) may in some cases be due to radical transfer reactions involving radicals formed on homolytic cleavage of the b-ether bond (Figure 2, reaction route C). The possibility that arylglycerols are liberated due to acid-catalysed enol ether cleavage during work-up procedures has also been considered (Lundquist 1973). To obtain knowledge about the stability of lignin structures of type 2 and arylglycerols (3) during alkaline pulping, we have studied the decomposition of guaiacylglycerol (4) and veratrylglycerol wthe erythro (9a) and threo forms (9b)x on soda cooking.

M1877 Two Functional Categories of Reflux-Inhibiting GABAB Receptor Agonists Defined By Their Affinity for the GABA Transporter

Background: Proton pump inhibitors (PPI) are the drug of first choice for treating patients with gastroesophageal reflux disease (GERD). However, about 50% of non-erosive reflux disease (NERD) patients have a poor response to PPI treatment. It is reported that esophageal motility disorder involving a decline in esophageal clearance contributes to the poor PPI response. Accordingly, a drug capable of enhancing esophageal motility would be beneficial in the treatment of NERD patients. Rikkunshito, a gastrointestinal prokinetic agent, is known to improve esophageal clearance in GERD patients and gastric emptying in functional dyspepsia patients and to increase secretion of ghrelin in rats. Aim: To clarify the efficacy of rikkunshito in NERD patients, we evaluated the effects of rikkunshito on esophageal and lower esophageal sphincter (LES) motility and symptoms. Methods: Fifteen patients were enrolled in the study. They were diagnosed as having NERD according to endoscopic testing and the score (6 points or more) obtained on the questionnaire for the diagnosis of reflux disease (QUEST). All patients stopped taking all gastrointestinal-related drugs for over 1 week prior to rikkunshito treatment, and were administered rikkunshito (7.5 g per day, orally) for 8 weeks. Esophageal and LES functions during liquid or semisolid swallow were evaluated using MII-EM following gold standard methods before and after rikkunshitotreatment. Symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS) before, 4 weeks after, and 8 weeks after treatment. Results: Rikkunshito-treatment significantly improved the mean of complete bolus transit (CBT) during liquid or semisolid swallow from 60.7±7.7% to 90.0±5.8% (p 79%, semisolid: >69%) for CBT decreased from 53.3% to 16.7% and from 60.0% to 33.3% after treatment, respectively. In manometry evaluation, rikkunshito significantly improved the mean of LES residual pressure during liquid swallow from 6.0±1.3 mmHg to 3.8±1.4 mmHg (p<0.05). In addition, rikkunshito significantly ameliorated total GI symptom scores in GSRS (from 2.1±0.2 to 1.6±0.1: (p<0.05)) and showed a tendency toward improvement of subscales for reflux symptoms, abdominal pain and dyspeptic symptoms. Conclusion: We found that rikkunshito improved the esophageal clearance and symptoms in NERD patients through the amelioration of esophageal and LES motility disorder. Thus, rikkunshito may become a useful drug for treating NERD patients.