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Magnus Nilsson,1 Magdalena Rhedin,2 Ramon Hendrickx,3 Susanne Berglund,1 Antonio Piras,2 Parmis Blomgran,2 Anders Cavallin,2 Mia Collins,2 Göran Dahl,4 Bilel Dekkak,5 Therese Ericsson,3 Niklas Hagberg,6 Ann Aurell Holmberg,3 Agnes Leffler,2 Anders J Lundqvist,3 Thomais Markou,5,7 James Pinkerton,5,7 Lars Rönnblom,6 Stacey Siu,8 Vanessa Taylor,8 Tiiu Wennberg,2 Dimitrios Zervas,5,7 Arian D J Laurence,9 Suman Mitra,2 Maria G Belvisi,5,7 Mark Birrell,5,7 Annika Borde2 1Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 2Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3DMPK, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Discovery Science, R&D, AstraZeneca, Gothenburg, Sweden; 5Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK; 6Rheumatology and Science for Life Laboratories, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 7Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 8Rigel Pharmaceuticals, South San Francisco, CA, USA; 9Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UKCorrespondence: Magnus Nilsson, Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SE-431 83, Sweden, Tel +46722237222, Email Magnus.Nilsson@astrazeneca.comPurpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 μg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.Keywords: AZD0449, AZD4604, JAK, STAT

Summary Background Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. Methods Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. Findings In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0–4h) from baseline to day 4; the increase in glucose AUC0–4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p Interpretation AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. Funding AstraZeneca.

Introduction: Asthma is a chronic inflammatory disease of the airways with typical symptoms manifesting in coughing, wheezing and dyspnoea. Whilst current treatments can be effective, some patients are not properly controlled, and the medications are not ideal and are associated with unwanted side effects. Thus, new therapies are urgently required. Typically, the chronic inflammation endotype is associated with increased levels of type 2 cytokine such as IL-4, IL-5, IL-9 & IL-13. These pro-inflammatory signalling pathways critically depend on Janus Kinase (JAK) I or II signal transduction, therefore the inhibition of JAK pathways represents a promising therapeutic target in asthma. Aims and Objectives: To assess the potential benefit of JAK inhibition using two structurally distinct inhibitors in a in vivo model system. Methods: Two JAK inhibitors, AZD4604 & AZD0449, were intratracheally dosed into sensitised Brown Norway rats one hour prior to aerosolised allergen (OVA) challenge. In one set of animals we assessed target engagement (TE) in the lung tissue by measuring levels of pSTATs. In a parallel set, we measured the Late Asthmatic Response (LAR) and lung inflammation. Results: Administration of both AZD4604 and AZD0449 resulted in dose related reduction of pSTAT3 and pSTAT5, indicating TE in the lung. Furthermore, AZD4604 & AZD0449 administration suppressed LAR and airway inflammation to a similar level to that achieved with the ICS comparator, budesonide. Conclusions: These data indicate that JAK inhibition may be of benefit to patients suffering from allergic asthma.

Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration-time profiles in lung tissue at the site of action to enable animal-to-man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross-species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups. The model is shown to allow translation between animal species and predicts drug concentrations in human lungs that correlate with the forced expiratory volume for different classes of bronchodilators. Thus, the pulmonary modeling approach has potential to be a key component in the prediction of human PK, efficacy, and safety for future inhaled medicines.

A structure-based design approach led to the identification of a novel class of indazole ether based, non-steroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-α release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small sub-set of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy.

Background: AZD9567 is a novel oral selective glucocorticoid receptor modulator (SGRM) developed to have an improved safety profile versus prednisolone while maintaining efficacy. Objectives: To show clinical evidence of safety differentiation for AZD9567 compared to prednisolone with respect to glucose homeostasis and to investigate the underlying effects on the glucose metabolism in human cell systems in vitro. Methods: In a dose escalation study (NCT02760316), healthy volunteers were randomized to a 5-day once-daily treatment with AZD9567 (20, 40, 80, 125 mg) or prednisolone (5, 20, 40 mg). We monitored the anti-inflammatory effect by TNFα release from ex vivo LPS stimulated whole blood and modelled the relationship with pharmacokinetics (PKPD). Plasma glucose was measured (AUC0–4h) during an oral glucose tolerance test (OGTT) before and after four days of treatment. We also studied the effects of AZD9567 and prednisolone on mRNA expression of key gluconeogenesis enzymes (tyrosine aminotransferease (TAT), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase)) in primary human hepatocytes as well as on insulin secretion in human islets microtissues. Results: The inhibition of TNFα release increased with the plasma concentrations of AZD9567. PKPD modeling of TNFα inhibition data showed that 40 mg AZD9567 results in an anti-inflammatory activity similar to that predicted for 20 mg prednisolone. A significantly smaller increase of the glucose AUC was observed following treatment with 20 to 125 mg AZD9567 compared to 20 mg prednisolone (p We found significant induction of TAT, PEPCK, and G6Pase mRNA in hepatocytes after prednisolone treatment. In contrast, AZD9567 did not change the expression of these enzymes and inhibited the effect of prednisolone when co-administered. Furthermore, AZD9567 showed less suppression of insulin secretion in human islets microtissues compared to prednisolone at concentrations with comparable inhibition of TNFα release, resulting in a 12-fold better therapeutic ratio. Conclusions: In healthy individuals, AZD9567 showed significantly reduced effect on glucose homeostasis versus prednisolone at doses with similar anti-inflammatory activity. Thus, AZD9567 shows potential as an anti-inflammatory treatment with an improved metabolic safety profile compared to prednisolone. Disclosure of Interest: T. Hegelund Myrback Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former emplyee), J. Leander Employee of: AstraZeneca, M. Hashemi Employee of: AstraZeneca, G. de Miquel Employee of: AstraZeneca (former emplyee), R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, Z. Tahib Employee of: AstraZeneca, E.-M. Andersson Employee of: AstraZeneca, P. Svanberg Employee of: AstraZeneca, K. Edman Employee of: AstraZeneca, R. Hendrickx Employee of: AstraZeneca, C. Keen Employee of: AstraZeneca, M. Kraan Employee of: AstraZeneca (former emplyee), K. Johansson Employee of: AstraZeneca (former emplyee), U. Eriksson Employee of: AstraZeneca, B. Carlsson Employee of: AstraZeneca, O. Vaarala Employee of: AstraZeneca

Background: Glucocorticoids (GC) are highly effective in the treatment of inflammatory diseases but chronic treatment is limited by severe adverse effects including hyperglycemia and bone re-modelling. AZD9567 is a novel, orally delivered, non-steroidal Selective Glucocorticoid Receptor Modulator (SGRM) with the potential to demonstrate an improved therapeutic ratio (TR) compared to steroidal GC such as prednisolone. Objectives: To investigate the effects of AZD9567 and prednisolone on biomarkers of inflammation, glucose metabolism and bone re-modelling in pre-clinical models. To confirm the inhibition of inflammatory biomarker production and to evaluate safety and pharmacokinetics (PK) of AZD9567 in a first clinical study. Methods: The effects on biomarkers of gluconeogenesis (tyrosine aminotransferase, TAT mRNA), bone re-modelling (osteoprotegerin, OPG mRNA) and anti-inflammatory activity (TNFα) were evaluated in vitro using human hepatocytes, an osteoblast cell line and whole blood, respectively. In vivo, effects on plasma insulin and osteocalcin levels were compared with inhibition of whole blood TNFα release in rats. Efficacy was evaluated in an adjuvant-induced rat arthritis model. In a human single ascending dose study the effect of AZD9567 on TNFα inhibition was investigated, together with assessment of safety profile and PK. Results: Potent in vitro anti-inflammatory activity (IC50,u6.2 nM, 7-fold more potent than prednisolone) was observed, whilst no effect on TAT mRNA expression in human hepatocytes was detected for AZD9567 (prednisolone EC5092 nM). This resulted in a substantially better TR compared to prednisolone. Furthermore, AZD9567 showed a 7-fold superior TR compared to prednisolone based on OPG mRNA expression in human osteoblasts. An improved profile for AZD9567 was also demonstrated in vivo in the rat (TR of 7.5 for osteocalcin and 3.6 for insulin). Efficacy was demonstrated in the rat arthritis model where an inhibition of joint inflammation was observed (ED500.1 mg/kg). In human, AZD9567 was safe and well tolerated after single doses (2–155 mg). The PK properties showed a fast absorption with a median tmax of 0.50 to 1.25 hour and a dose-dependent increase in exposure, with a mean terminal half-life of 3.9 to 6.4 hours, suitable for a once daily dosing regimen. TNFa release was inhibited in a concentration-dependent manner (IC50,u5.2 nM), consistent with pre-clinical findings. Conclusions: In pre-clinical models, AZD9567 demonstrated anti-inflammatory activity with a reduced effect on gluconeogenesis and biomarkers of bone re-modelling compared to prednisolone. Single oral dosing of AZD9567 was well tolerated and showed good PK properties in healthy subjects. These results support that AZD9567 has the potential to improve the treatment of several inflammatory diseases with a better TR compared to prednisolone. AZD9567 is currently in clinical evaluation in rheumatoid arthritis. Disclosure of Interest: R. Hendrickx Employee of: AstraZeneca, T. Hegelund-Myrback Employee of: AstraZeneca, M. Dearman Employee of: AstraZeneca, S. Prothon Employee of: AstraZeneca, G. Edenro Employee of: AstraZeneca (former employee), J. Leander Employee of: AstraZeneca, R. Fuhr Employee of: Parexel International GmbH, T. Kornicke Employee of: Parexel International GmbH, P. Svanberg Employee of: AstraZeneca, A. Berggren Employee of: AstraZeneca, T. Drmota Employee of: AstraZeneca (former employee), C. Keen Employee of: AstraZeneca, U. Eriksson Employee of: AstraZeneca

Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration‐time profiles in lung tissue at the site of action to enable animal‐to‐man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross‐species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups. The model is shown to allow translation between animal species and predicts drug concentrations in human lungs that correlate with the forced expiratory volume for different classes of bronchodilators. Thus, the pulmonary modeling approach has potential to be a key component in the prediction of human PK, efficacy, and safety for future inhaled medicines.

Recently the clinical importance of human organic cation transporters 1 (hOCT1/SLC22A1) and 2 (hOCT2/SLC22A2) in drug disposition, for example, clearance, toxicity, and drug-drug interactions, have been highlighted [Annu. Rev. Pharmacol. Toxicol. 2012, 52, 249-273; Nat. Rev. Drug Discovery 2010, 9 (3), 215-236]. Consequently, there is an extensive need for experimental assessment of structure-transport relationships as well as tools to predict drug uptake by these transporters in ADMET (absorption, distribution, metabolism, excretion, toxicity) investigations. In the present study, we developed a robust assay for screening unlabeled compound uptake by hOCT1 and hOCT2 using transfected HEK293 cells. For the first time, an extensive data set comprising uptake of 354 compounds is presented. As expected, there was a large overlap in substrate specificity between the two organic cation transporters. However, several compounds selectively taken up by either hOCT1 or hOCT2 were identified. In particular, a chemical series of phenylthiophenecarboxamide ureas was identified as selective hOCT1 substrates. Moreover, the drivers for transport differed: molecular volume was the most important determinant of hOCT1 substrates, whereas H-bonding parameters like polar surface area (PSA) dominated for hOCT2.

The oxidations of alkyl 4-nitrophenyl, and dialkyl, sulfides and sulfoxides by dimethyldioxirane in acetone occur by concerted mechanisms but the sulfides respond differently from the sulfoxides to variation in the alkyl group. The reactions of the sulfides are inhibited by the steric effects of alkyl groups and these predominate over their inductive effects. By contrast, the reactions of these limited sets of sulfoxides are insensitive to alkyl steric effects but there is an indication of steric acceleration when a broader set of sulfoxides is considered. This behaviour is rationalised in terms of the differences in dipolar charge and its solvation between the ground state and transition state for the two types of substrate. The oxidations of cyclic sulfides and sulfoxides also exhibit contrasting behaviour. The reactivity of the sulfides is insensitive to ring strain but is explicable in frontier orbital terms whereas that of the sulfoxides is partly dependent upon the change in ring strain between reactant and product on oxidation, a difference rationalised in terms of the relative positions of the transition states in the reaction coordinates of the two oxidations. The reactivity of 4-, 5- and 6-membered cyclic sulfoxides is also dependent on a ring-size related property of the transition state. Calculations at the B3-LYP/6-31G* level of density functional theory on both ground states and transition states, including simulation of solvation by acetone, strongly support the mechanistic conclusions reached in this and earlier work.

Simple and rational: The intrinsic solubility of a compound can be systematically improved by perturbing key interactions in its crystal structure. By carefully choosing the perturbation, the end r ...

The photochemical reactions of styrene, (E)-stilbene, phenyl-ethyne, and diphenylethyne with pyrrole and N-methylpyrrole have been investigated. The pyrroles quench the fluorescence of the phenylethenes and phenylethynes efficiently and broad structureless emissions attributed to exciplexes are observed from the N-methylpyrrole systems. Substituted pyrroles (1:1 and 2:1 adducts) are formed from irradiation of the phenylethenes with pyrrole, and 2-styrylpyrroles result from the phenylethynes. Styrene, but none of the other arenes, undergoes photoaddition to N-methylpyrrole in the presence of 10% acetic acid.

The photochemical reactions of styrene, (E)-stilbene, phenyl-ethyne, and diphenylethyne with pyrrole and N-methylpyrrole have been investigated. The pyrroles quench the fluorescence of the phenylethenes and phenylethynes efficiently and broad structureless emissions attributed to exciplexes are observed from the N-methylpyrrole systems. Substituted pyrroles (1:1 and 2:1 adducts) are formed from irradiation of the phenylethenes with pyrrole, and 2-styrylpyrroles result from the phenylethynes. Styrene, but none of the other arenes, undergoes photoaddition to N-methylpyrrole in the presence of 10% acetic acid.

Relative rate constants have been measured for the oxidation of aryl methyl sulfides and sulfoxides by dimethyldioxirane in acetone, in mixtures of acetone with aprotic co-solvents of both higher and lower relative permittivity, and in aqueous acetone mixtures. Correlation analyses of the effects of substituents in the different solvents show that, with one exception, reactions take place via a single step mechanism in which the formation of the new SO bond and the elimination of acetone occur concertedly. The exception was oxidation of the sulfides in aqueous acetone containing the highest proportion of water of those studied (20% v/v). Here, the behaviour of the reaction is consistent with a two-step mechanism in which the oxidant reversibly attacks the sulfide to form an open-chain sulfonium betaine that subsequently fragments to sulfoxide and acetone. There is no evidence for the participation of an intermediate dioxathietane as has been found in the case of sulfide oxidations by (trifluoromethyl)methyldioxirane in CH(2)Cl(2) and similar aprotic solvents. It is not justified to generalise a mechanism involving a betaine, with or without a derived dioxathietane, to the reactions of dimethyldioxirane in acetone.

The oxidations of methyl 4-nitrophenyl sulfide and sulfoxide by dimethyldioxirane, in acetone and mixtures of acetone with water, methanol, acetonitrile and hexane, have been followed by UV-Vis spectroscopy to monitor the decay of the substrates. The data show that, under all the conditions studied, both oxidations obey second-order kinetics. Grunwald-Winstein and Kamlet-Taft analyses of the influence of solvents on the second-order rate constants have been used to obtain mechanistic information on the two reactions. Activation parameters for the two oxidations in acetone and aqueous acetone have been calculated from rate constants for reactions in the temperature range 283-313 K and compared with those from sulfide and sulfoxide oxidations with other oxidants. For sulfoxide oxidations in acetone and 1-20% v/v water in acetone, the results support a concerted nucleophilic displacement by sulfur of oxygen from dimethyldioxirane with the rate being dependent on the solvent's polarity. Sulfide oxidations in acetone and 1-5% v/v water in acetone also proceed by a concerted mechanism. However, in the most polar solvent system studied, 20% v/v water in acetone, the mechanism changes in favour of a two-step reaction involving a betaine intermediate. Importantly, the sulfide oxidation shows a different solvent dependence to that of the sulfoxide, with the rate of oxidation being determined by the hydrogen bond donor capacity and electron-pair donicity of the solvent.