Spirooxindoles derivatives as novel inhibitors of the respiratory syncytial virus

Respiratory Syncytial Virus (RSV) is an important pathogen that affects the lower respiratory track resulting in hospitalisation in infants and young children and is a significant cause of morbidity and mortality in the elderly and immunocompromised patients. The RSV F protein plays a crucial role in the life cycle of the virus and its entry into the host cells. Once the fusion has been initiated, it causes a series of conformational changes facilitating the fusion of the virus with the host’s cellular membranes which eventually leads to releasing viral RNA strands into the host cells. Disruption of the viral envelop and in particular of the RSV F protein by small molecules has been shown to be efficacious in the treatment of RSV infection in rodent models. Small molecule inhibitors of the RSV fusion protein have been reported over the last 15 years and several compounds have progressed into early clinical development but none have reached the market. RV-39 had previously been reported as a RSV fusion inhibitor, exhibiting excellent in vitro antiviral activity in both the fusion and plaque reduction assays. Although RV-39 showed good stability in rat liver microsomes, the compound showed high clearance in human liver microsomes. Furthermore, RV-39 showed high plasma clearance and low bioavailability when progressed to a rat pharmacokinetic study. In this work, a series of novel 3,3’-spirocyclic oxindoles and aza-oxindoles were designed and synthesised as potential RSV fusion inhibitors, aiming to improve on human liver microsomes and on the pharmacokinetic profile of RV-39 in rat. Novel chemistry was established to synthesise the spirocyclic oxindoles and aza-oxindoles via a palladium catalysed -arylation of 2-bromo anilides as the key synthetic step. The scope of the reaction was explored, demonstrating that access to spirocyclic oxindoles could be obtained in good to excellent yield from readily available carboxylic acids and 2-bromo anilines. Conditions for the removal of the para-methoxybenzyl protecting group were optimised to enable the preparation of a series of analogues with potent antiviral activity against the RSV virus The novel compounds prepared demonstrated excellent antiviral potency in both the fusion and the plaque reduction cellular assays and also showed improved metabolic stability in human liver microsomes compared to RV-39. A selection of compounds was further profiled in in vivo rat pharmacokinetic studies and the preliminary results suggested that whilst the plasma clearance remained high, good half-life and significant improvement in bioavailability compared to RV-39 could be achieved across this novel series of compound

An atom-efficient and convergent approach to the preparation of NS5A inhibitors by C-H activation

A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C–H activation is reported. The focus of investigation was to reduce the formation of homodimeric side product, as well as to investigate the scope of different aryl dibromides that were tolerated under the reaction conditions. The C–H activation methodology was found to give a viable synthetic route to NS5A inhibitors, with late stage functionalisation of the core portion of the molecule, albeit with some chemical functionalities not tolerated

Incorporation by coordination and release of the iron chelator drug deferiprone from zinc-based metal–organic frameworks

A series of new zinc-based metal–organic framework materials has been prepared in which deferiprone is incorporated as a chelating ligand on infinite or tri-zinc secondary building units following deprotonation. Deferiprone is immediately released from the MOFs on treatments with 1 N hydrochloric acid or buffer, but slow release is observed in ethanoic acid

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABAARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABAARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed

Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors of the mouse nucleus accumbens

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABAARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABAARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed

African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase

African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead

Improved results of lung transplantation for patients with cystic fibrosis

AbstractPatients with cystic fibrosis pose particular challenges for lung transplantation surgeons. Earlier reports from North America centers suggested that patients with cystic fibrosis were greater risk for heart-lung or isolated lung transplantation than other patients with end-stage pulmonary disease. During a 3 ½ year period, 44 patients with end-stage lung disease resulting from cystic fibrosis underwent double lung transplantation at this institution. During the same interval, 18 patients with cystic fibrosis, died while waiting for a double lung transplantation. The ages of the recipients ranged from 8 to 45 years, and mean forced expiratory volume in 1 second was 21% predicted. Seven patients had Pseudomonas cepacia bacteria before transplantation. Bilateral sequential implantation with omentopexy was used in all patients. There were no operative deaths, although two patients required urgent retransplantation because of graft failure. Cardiopulmonary bypass was necessary in six procedures in five patients and was associated with an increased blood transfusion requirement, longer postoperative ventilation, and longer hospital stay. Actuarial survival rate was 85% at 1 year and 67% at 2 years. Infection was the most common cause of death within 6 months of transplantation ( Pseudomonas cepacia pneumonia was the cause of death in two patients), and bronchitis obliterans was the most common cause of death after 6 months. Actuarial freedom form development of clinically significant bronchiolitis obliterans was 59% at 2 years. Results of pulmonary function tests improved substantially in survivors, with forced expiratory volume in 1 second averaging 78% predicted 2 years after transplantation. Double lung transplantation can be accomplished with acceptable morbidity and mortality in patients with cystic fibrosis. (J THORAC CARDIOVAS SURG 1995;109-:204-35

Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2

TDP2 is a 5’-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II. TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for HTS-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanised’ form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2

Discovery of sisunatovir (RV521), an inhibitor of respiratory syncytial virus fusion

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo