David R. Witty

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.

Advances in the design of 5-HT6 receptor ligands with therapeutic potential.

Publisher Summary The serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system in the brain plays a key role in a range of central functions including cognitive, motor, sensory, and affective functions, as well as sleep and appetite, and has therefore been the focus of drug-discovery efforts. Several cognitive paradigms help to examine the roles of 5-HT 6 receptor antagonists. The potential therapeutic effects of 5-HT 6 receptor antagonists on behavioral symptoms, such as anxiety and depression, have been examined. Receptor knockdown by anti-sense oligonucleotides and the receptor antagonist reduced food consumption and body weight, suggesting a role for the 5-HT 6 receptor in the regulation of feeding. The pre-clinical data provided strong rationale for the extensive medicinal chemistry campaigns that ensued in multiple companies to develop brain-penetrant ligands for the 5-HT 6 receptors. The chapter describes the medicinal chemistry of 5-HT 6 to compare the specific approaches of different institutions to discovering, optimizing, and exploiting the 5-HT 6 receptor ligands, focusing on scientific publications and patent applications. The chapter discusses 5-HT 6 receptor modulation and the approaches targeting dual 5-HT 6 and second receptor modulation. The basic understanding of the role of the receptor in human physiology has improved and the number of potential therapeutic areas that could be impacted by 5-HT6 receptor agonism or antagonism continues to increase, especially in the fields of neurology and psychiatry.

Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.

Crystal Structures of Ask1-Inhibtor Complexes Provide a Platform for Structure Based Drug Design.

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a ‘replacement‐soaking’ method that has enabled the high‐throughput X‐ray structure determination of ASK1/ligand complexes. Comparison of the X‐ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement‐soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

Structure-activity dependency of new bacterial tryptophanyl tRNA synthetase inhibitors

Abstract Analogues of the aminoacyl tRNA synthetase inhibitor, indolmycin, have been synthesised in which the side chain methyl group is replaced by a wide range of substituents. Their antibacterial and enzyme inhibitory potency is related to steric properties and conformational preferences.

P4-327: Effects of the novel 5-HT6 SB-742457 antagonist and the cholinesterase inhibitor donepezil in models of cognition

related to aging, Alzheimer’s disease (AD) and Schizophrenia. Thus serotonergic system became a potential target for the treatment of memory dysfunction. Methods: Our effective lead generation and optimization methods have resulted in a potent 5-HT6 receptor antagonist SUVN-502 with Ki of 1.71 nM. SUVN-502 exhibited antagonist like inhibition with EC50 of 0.103 M when tested for functional activity. SUVN-502 has more than 100 fold selectivity against the related GPCRs. The effective optimization of its critical physico-chemical properties has lead to oral bioavailability (31%) and brain penetration index (1.48). Results: SUVN-502 was effective in animal models of cognition. SUVN-502 reversed the age induced memory deficit in Morris water maze and novel object recognition task (NORT). SUVN-502 also reversed the spatial and working memory deficit induced by MK-801 and scopolamine in Morris water maze, NORT and radial arm maze task. The effective dose range of SUVN-502 in the above animal models was between 3 to 10 mg/kg. p.o. Brain microdialysis studies in rats with SUVN-502 showed significant increase in brain acetylcholine and glutamate levels correlating to the in vivo memory models. Conclusions: SUVN-502 has been identified as a candidate for clinical development for the symptomatic treatment of Alzheimer’s disease. SUVN-502 has completed all regulatory safety and toxicity studies to enter to human Phase-I clinical trials in 2008.