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Faculty Alexander C. Humphries The GABA-A receptor complex incorporates a Cl - ion-channel and plays a crucial role in controlling brain excitability. As with many other ligand-gated ionophores, the structure of the complex is pentameric, generally comprising two a subunits (selected from a 1-6 ), co-assembled with two b subunits (from b 1-3 ) and a single g subunit (from g 1-3 ). In addition to the two primary g -aminobutyric acid (GABA) binding sites, the complex possesses a number of allosteric receptors which modulate the effect of GABA binding. Therapeutically, the most important of these is the site of action of classical benzodiazepines such as Diazepam (see below). This ‘benzodiazepine (BZ) receptor' is expressed on GABA-A complexes in situations where an a 1 , a 2 , a 3 , or a 5 unit is interfaced with a g 2 unit. Hence, the four subtypes of the BZ receptor are named after their a subunit. Diazepam is well known for its potent anxiolytic and anti-convulsant properties, although these are accompanied by side effects such as memory loss and sedation. All of these properties are the result of non-selective agonist activity at all four a subtypes of the BZ receptor and it is only recently that transgenic and pharmacological advances have provided insights into the functional differentiation of the subtypes. For example, it is now generally accepted that agonist activity at a 1 receptors is the principal cause of sedation, although the contribution of a 2 - versus a 3 -containing BZ receptors to the anxiolytic and anti-convulsant activity of diazepam has been the subject of some controversy . Over the last few years, we have conducted a medicinal chemistry programme aimed at developing selective BZ receptor ligands as non-sedating anxiolytics. During the course of these studies, we identified compound 1 (shown below), an a 3 -subtype selective GABA-A/BZ receptor agonist. This compound is of particular interest as its selectivity profile makes it a valuable tool in determining the anxiolytic influence of a 3 using in vivo behavioural paradigms.
This presentation will describe the medicinal chemistry leading to 1 , with an emphasis on the synthesis and properties of the versatile 8-fluoroimidazo[1,2- a ]pyridine core. The behavioural effects of 1 in both rodent and non-human primate anxiolysis models will then be discussed in the context of the compound's in vitro properties. Andy Boyd Hedgehog proteins and the foundation of small molecule modulators The Hedgehog (Hh) family of proteins plays an essential role in embryonic development. There are a series of protein ligands for the receptor including; Sonic (SHh), Indian (IHh), and Desert (DHh) which show very high interspecies homology, from species as diverse as Drosophila and man. The Hh protein receptor, Patched-1 (Ptch-1), is a transmembrane protein with a structure reminiscent of that found in ion channels. Ptch-1 inhibits Smoothened (Smo), a receptor structurally similar to G protein coupled receptors. Upon binding of an Hh protein ligand to Ptch-1, the normally inhibited Smo is disinhibited, and it activates the nuclear transcription factor Gli-1 via a signaling cascade. The three Hedgehog ligands, SHh, IHh, and DHh, are morphogens which have different roles in embryogenesis. Thus, IHh affects cartilage and bone development, SHh influences neuronal development in the CNS, and DHh regulates peripheral neuronal development. Mutations which activate the Hh pathway produce basal cell carcinoma (BCC) and meduloblastoma, a cancer which is rare but invariably fatal. In addition, Hh proteins are over expressed by, and stimulate proliferation of tumor cells in pancreatic and GI tumors. The Hh pathway is essential for the formation of normal nerves in the central and peripheral nervous system. It has been shown that treatment with a Hh protein accelerates the restoration of nerve function in models of trauma and disease 4 . This indicates that the Hh pathway may have a potential therapeutic effect in treating certain neurological disorders (e.g. stroke, Parkinson's disease, spinal cord injury and diabetic neuropathy). While two complex natural products, jervine and cyclopamine act upon the Hh pathway, tractable, small molecule modulators of this pathway have been lacking. Thus, the Hedgehog pathway is a fertile, but unexploited opportunity for therapeutic intervention. The presentation will introduce a series of modulators of the Hh pathway that have been discovered through high throughput screening. Biaryl derivatives showing agonist in vivo activity and amino-proline derivatives showing antagonist in vivo activity will be discussed with outline SAR. The agonist and antagonist modulators presented represent the first small molecule modulators reported in the patent literature. Small molecule modulation of the Hh pathway is in its infancy and the molecules presented provide useful tools to further probe the function of the pathway. In addition, there is emerging evidence that modulation of the Hh pathway offers important therapeutic potential for treatment of a variety of diseases. Andrew J. Ratcliffe Design of novel IMPDH II inhibitors Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis pathway of guanine nucleotides. Two isoforms of the enzyme have been identified and designated type I and type II. Proliferating cells depend heavily on continued access to a pool of guanine nucleotides and in order to meet this demand IMPDH II is upregulated. Mycophenolic acid (MPA) is a potent, uncompetitive reversible inhibitor of both IMPDH I and II, which in the form of a prodrug, is approved for transplant rejection. However, the reported gastrointestinal toxicity of MPA has resulted in the search for alternative IMPDH II inhibitors with improved therapeutic windows for treatment in autoimmune diseases such as psoriasis, systemic lupus erythematosus and rheumatoid arthritis. Towards this end several oxazole based IMPDH II inhibitors have been reported and progressed to clinical studies. Several series of potent and novel oxazole based IMPDH II inhibitors have been developed at Celltech and will be described. The discovery that the oxazole moiety represented a potential bioactivation liability led to the design of a potent non-oxazole based series utilising a fragment based approach. Anthony Wood This presentation describes the drug discovery programme that lead to the identification of UK-427,857, a prototype CCR5 antagonist with excellent potency against lab-adapted and primary virus strains, as a clinical candidate for the treatment of HIV. In particular, it deals with strategies for minimising cardiac toxicity whilst maintaining ADME properties commensurate with low dose. UK-427,857 The presentation will cover aspects of the following areas of the programme.
Simon Ward Multiple 5-HT approaches to novel anti-depressants Extensive pre-clinical and clinical data links the enhancement of serotonergic neurotransmission with the anti-depressant action of the both the newer class of selective serotonin reuptake inhibitors (SSRIs) as well as the older classes of monamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. Considerable research has been carried out to investigate other 5-HT targets associated with the disease and studies involving combination treatments with selective serotonin reuptake inhibitors and 5-HT 1 receptor ligands have been carried out in the clinic. Starting from the high throughput screening hit 1 with affinity for the 5-HT 1A receptor, a chemical series has been developed which displays a range of affinities across the 5-HT 1 receptor subtypes and the serotonin transporter. The chemistry and SAR of this series is presented together with the medicinal chemistry strategies employed.
[1] Middlemiss, D. N., Price, G. W., Watson, J. M. Serotonergic targets in depression. Current Opinion in Pharmacology 2002, 18-22. [2] Atkinson, P. J., Bromidge, S. M., Coleman, T., Duxon, M. S., Gaster, L. M., Hadley, M. S., Hammond, B., Johnson, C. N., Middlemiss, D. N., North, S. E., Price, G. W., Rami, H. K., Riley, G. J., Scott, C. M., Shaw, T. E., Starr, K. R., Stemp, G., Thewlis, K. M., Thomas, D. R., Thompson, M., Vong, A. K. K., and Watson, J. M. 3,4-Dihydro-2H-benzoxazinones as 5-HT1A receptor ligands with potent 5-HT reuptake inhibitory activity . Bioorganic & Medicinal Chemistry Letters in press. Jeremy N. Burrows High Concentration Screening: Integrated Lead Generation High-throughput screening (HTS) at a concentration of 10 m M is an established technology throughout the industry in the search for potent “hits” of a biological target. HTS therefore relies heavily on the quality of the compound collection and assumes that potent “hits” are always present and waiting to be found. Despite the success of HTS, numerous targets have failed to yield attractive chemical start-points. This presentation will detail an integrated strategy to screen biological targets at concentrations up to 1mM. Examples from several inhouse projects that validate the approach will be shown.
Roger Crossley Rho kinase alpha (ROK, ROCK2) is a serine/threonine kinase that is activated by association with the small GTP-binding protein Rho. ROK is implicated in the pathogenesis of a number of indications. In vitro and in vivo studies with first generation ROK inhibitors have shown beneficial effects in models of cardiovascular disease, stroke, cancer, glaucoma, erectile dysfunction and nerve growth and repair. Fasudil, a kinase inhibitor with some selectivity towards ROK, is marketed in Japan for the treatment of vasospasm and has recently been shown to be effective in the treatment of stable angina in clinical trials. Inhibition of ROK therefore has a multiplicity of potentially useful therapeutic outcomes with no apparent target related safety issues in humans and hence is an increasingly interesting therapeutic target. We have, for a number of years now been producing and marketing focused screening libraries directed at kinases. Use of such libraries provides a highly cost effective and efficient means of developing lead series following screening exercises. We decided to apply a selection of these libraries to the task of developing ROK inhibitors and rapidly achieved a series of selective and bioavailable compounds. |
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