Andrew William Thomas

Reducing GABAA α5 Receptor-Mediated Inhibition Rescues Functional and Neuromorphological Deficits in a Mouse Model of Down Syndrome

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABAA α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABAA α5 NAMs to treat cognitive dysfunction in DS.

Characterization of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one as a positive allosteric modulator of GABAB receptors

As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one (rac‐BHFF) as enhancers of GABAB receptors.

The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA α5 inverse agonists for the treatment of cognitive dysfunction

Lead optimisation of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 (11) and RO4938581 (44)] functioning as novel potent and selective GABAA alpha5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.

A concise route to triazolobenzodiazepine derivatives via a one-pot alkyne-azide cycloaddition reaction.

A new and efficient one-pot synthesis of [1,2,3]triazolo[1,5-a][1,4] benzodiazepin-6(4H)-ones is described starting from readily available anthranilic acids. A small array of the title compounds were assembled via a four-step sequence involving diazotisation, azide addition followed by amide bond formation employing polymer supported carbodiimide and subsequent 1,3-dipolar cycloaddition reaction.

The positive allosteric modulator of the GABAB receptor, rac-BHFF, suppresses alcohol self-administration

The present study was designed to extend to the newly synthesized rac-BHFF [(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one] the investigation on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol self-administration in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (0.7%, w/v) in daily 30-min sessions. Once responding reached stable levels, the effect of rac-BHFF (0, 50, 100, and 200mg/kg; i.g.) on responding for alcohol and sucrose was determined. Pretreatment with rac-BHFF produced a dose-dependent suppression in responding for alcohol; reduction in the total number of responses for alcohol, in comparison to vehicle-treated rats, averaged approximately 30%, 65%, and 90% in 50, 100, and 200mg/kg rac-BHFF-treated rats, respectively. Pretreatment with 200mg/kg rac-BHFF markedly increased the latency to the first response on the alcohol lever. The effect of pretreatment with rac-BHFF on alcohol self-administration was highly specific, since (a) responding for sucrose was reduced (to approximately 50%, in comparison to vehicle-treated rats) only by pretreatment with 200mg/kg rac-BHFF, and (b) latency to the first response on the sucrose lever was completely unaltered by any rac-BHFF dose. Treatment with rac-BHFF did not alter spontaneous locomotor activity in an independent group of sP rats. The present data constitute a further piece of evidence on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohols reinforcing properties in rats.

Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors

Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.

Modified mesoporous silicate MCM-41 materials: immobilised perruthenate—a new highly active heterogeneous oxidation catalyst for clean organic synthesis using molecular oxygen

A new oxidation catalyst containing perruthenate immobilised within MCM-41 has been prepared and used in the clean oxidation of alcohols to carbonyl compounds with molecular oxygen.

Organic synthesis provides opportunities to transform drug discovery

AbstractDespite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C–H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C–X or C–C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.Organic synthesis is a rate-limiting factor in drug discovery, so the pharmaceutical industry heavily relies on academic research. This Perspective highlights some of the most pressing challenges to be overcome from the industrial viewpoint — such as the development of reactions tolerating specific functionalities — and encourages stronger industry–academia relationships. Credit: Pills image: Profimedia.CZ a.s. / Alamy Stock Photo; Factory image: Diana Johanna Velasquez / Alamy Stock Vector; Graduate hat: Michael Burrell / Alamy Stock Photo; Conical flask: Astex.

Synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents

The concise synthesis of the alkaloids (±)-oxomaritidine 1 and (±)-epimaritidine 2 in high yield are described, which employs a sequence of five- and six-step reactions respectively, using solely polymer supported reagents in an orchestrated successive manner.

Polymer-supported hypervalent iodine reagents in ‘clean’ organic synthesis with potential application in combinatorial chemistry

A clean oxidation reaction of a variety of substrates using polymer-supported (diacetoxyiodo)benzene (PSDIB) which proceeds in high to excellent yield with maximum purity is described including isolation and regeneration of the polymer reagent.