Francis X. Wilson

Iminosugars past, present and future: medicines for tomorrow.

Iminosugars comprise the most attractive class of carbohydrate mimetics reported to date and are ideally positioned to take advantage of our increasing understanding of glycobiology in the search for new medicines. First-generation iminosugar drugs suffered from lack of adequate selectivity, resulting in considerable side-effects in the clinic. Current efforts directed towards second-generation compounds, encompassing a much greater range of structures and addressing a wider selection of biochemical targets, are enabling the identification and development of suitable candidates that benefit from improved activity and selectivity. Furthermore, second-generation compounds can address a variety of established targets that have previously proved refractory to other compound classes. This review focuses on the breadth of opportunities provided by second-generation leads from iminosugars (Seglins™).

Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse

Background Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle. There is significant evidence demonstrating that increasing levels of the dystrophin-related protein, utrophin, in mouse models results in sarcolemmal bound utrophin and prevents the muscular dystrophy pathology. The aim of this work was to develop a small molecule which increases the levels of utrophin in muscle and thus has therapeutic potential. Methodology and Principal Findings We describe the in vivo activity of SMT C1100; the first orally bioavailable small molecule utrophin upregulator. Once-a-day daily-dosing with SMT C1100 reduces a number of the pathological effects of dystrophin deficiency. Treatment results in reduced pathology, better muscle physiology leading to an increase in overall strength, and an ability to resist fatigue after forced exercise; a surrogate for the six minute walk test currently recommended as the pivotal outcome measure in human trials for DMD. Conclusions and Significance This study demonstrates proof-of-principle for the use of in vitro screening methods in allowing identification of pharmacological agents for utrophin transcriptional upregulation. The best compound identified, SMT C1100, demonstrated significant disease modifying effects in DMD models. Our data warrant the full evaluation of this compound in clinical trials in DMD patients.

Therapeutic Applications of Iminosugars: Current Perspectives and Future Opportunities

Publisher Summary The understanding of the role of carbohydrates, their receptors, and their handling processes in the functioning of biological systems is an area in which major advances have been made during the past 20 years. The diverse structures displayed by carbohydrates provide a substantial opportunity for the identification of new chemotherapeutic targets and the development of new therapies. This has motivated both synthetic and medicinal chemists in the pursuit of new medicines although carbohydrates themselves can rarely be employed for this purpose owing to their metabolic instability and rapid degradation in vivo . As a consequence, researchers have focused on the design and synthesis of carbohydrate mimetics with greater stability, affinity, and efficacy. Iminosugars are the most attractive class of carbohydrate mimetics reported to date and are ideally positioned to take advantage of the increasing understanding of this area. The chapter summarizes the status of the iminosugar field providing an overview of the classification, occurrence, and synthesis of iminosugars, before discussing in detail the therapeutic potential of this class of molecule.

Synthesis and glycosidase inhibition of the enantiomer of (-)-steviamine, the first example of a new class of indolizidine alkaloid.

(+)-Steviamine, the enantiomer of the natural (-)-steviamine, and its corresponding C5 epimer have been synthesized from the D-ribose-derived cyclic nitrone. (-)-Steviamine was found to be the first naturally occurring iminosugar that causes any inhibition of alpha-galactosaminidases.

Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy.

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

Solid phase synthesis of aminoboronic acids: potent inhibitors of the hepatitis C virus NS3 proteinase

Use of a resin bound diol as a boronic acid protecting group has been developed to allow the parallel synthesis of potent inhibitors of the hepatitis C virus NS3 serine proteinase.

Asymmetric induction using atropisomers: Diastereoselective additions to 2-acyl-1-naphthamides

Abstract The amide group of 2-acyl- N , N -dialkyl-1-naphthamides, twisted perpendicular to the naphthyl ring, controls the stereoselectivity of attack of nucleophiles on the 2-substituent. Selectivities of >140:1 may be achieved with bulky nucleophiles, which attack anti to the N , N -dialkyl group.

Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition

The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.

Controlling the regioselectivity of lithiation using kinetic isotope effects: Deuterium as a protecting group for carbon

Abstract By substituting deuterium for hydrogen at positions of high kinetic acidity in amides and carbamates, the usual regiochemical course of their reactions with alkyllithiums (ortholithiation vs. lateral lithiation vs. nucleophilic addition) can be altered or overturned by the kinetic isotope effect. The deuterium substituent functions in these reactions as a protecting group for carbon.

Second-generation compound for the modulation of utrophin in the therapy of DMD

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.