Cns drug discovery: challenges and solutions

Available on the web at: Highlights from the Society for Medicines Research symposium held September 23, 2004, in London, United Kingdom.
The worldwide market for therapies for central nervous system (CNS) disorders was valued at around $50 billion in 2001, and is set to grow sharply in the years ahead. This is because of a marked increase in the number of people aged over 65 (the “baby boomer” effect), which will lead to increased demand for more safe and effective The World Health Organization medicines for CNS disorders. This one-day Society for Medicines Research sympo- sium, held September 23, 2004, in London, United Kingdom, was organized by Dr. Alan M. Palmer (Pharmidex, London, U.K.) and Prof. F. Anne Stephenson (School of Pharmacy, University of London, U.K.). More than 100 delegates heard a scholarly and comprehensive review of the challenges currently facing CNS research and develop- ment, which was accompanied by consideration of a variety of innovative solution strategies. The meeting considered: 1) how to identify and validate targets for poten- tial CNS drugs; 2) how to assess brain penetration (both in vitro and in vivo); 3) how to develop in silico methodologies to predict blood–brain barrier penetration; 4) how to assess therapeutic efficacy (both in vitro and in vivo); 5) how to establish reliable bio- markers to guide decision making; and 6) how to effectively apply magnetic resonance imaging to CNS drug discovery. 2005 Prous Science. All rights reserved.
with sales in excess of $50 billion.
cant challenges. These are exemplified bility of success.
Copyright 2005 Prous Science. CCC: 0214-0934/2005 TABLE II: THREE GENERATIONS OF ANTIPSYCHOTIC DRUGS pies to enhance cholinergic function.
neurological effects. This has led to the A.M. Palmer and F.A. Stephenson pp. 51–57 TABLE III: TWO GENERATIONS OF ACETYLCHOLINESTERASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER’S DISEASE provides an indicator of brain partition, provide a full PK profile (i.e., Cmax, went on to explore the physicochemi- cal determinants of brain penetration.
activity relationship for this transporter seal of cells that lines the blood vessels medicines for the treatment of pain.
(because of their tight junctions), these A.M. Palmer and F.A. Stephenson pp. 51–57 have utility in the treatment of pain.
which are the best remains a challenge.
nist that was recently approved in Europe and the United States for the treatment of moderate to severe Alzheimer’s disease. It represents the first and only representative of a new class of drug for this disorder.
dictive validity? It is also possible that fore provide broad-spectrum analgesia.
antagonists in clinical trials for stroke.
preclinical data is a major challenge for also not clear if it is sufficient to block is a great need for reliable in vitro mod- channels need to be blocked as well.
reproduced in clinical trials. Similarly, A.M. Palmer and F.A. Stephenson pp. 51–57 a description of GABAA receptor sub- tory behavior in the α1H101R animals; discovery. An example of the benefits mals. L-838417, an antagonist at the α1 ies of NR1 knockout animals: the subtype and an agonist at the α2/3/5 sub- homozygote knockout is lethal, where- ties, on the basis of activity in the rotar- possible to establish that certain behav- 1βγ2, α2βγ2, α3βγ2 and α5βγ2.
site alterations to dissect out the vari- the targets of the 100 best-selling drugs side-effect profile over the current gen- trials, 2–3 years in phase 2, 3–4 years sign used as a substitute for a clinical- Fig. 2. L-838417 is an antagonist at the α1- and side-effect liability than is possible subunit containing GABAA receptor subtype A.M. Palmer and F.A. Stephenson pp. 51–57 in a clinical trial for stroke. Since lon- tion is sufficiently promising to justify tive process, it also provides a key tool term and more expensive clinical trials.
approval of β seron by the U.S. FDA.
It has also been used to “visualize” tis- changes in patients following a stroke.
for marker sensitivity, specificity, pos- activation in a number of cortical areas.
early stages of CNS drug development.
possible to select patients with a corti- they are particularly needed for clinical A.M. Palmer and F.A. Stephenson pp. 51–57 specificity for novel antipsychotics.
protective in several in vitro models of neu- rodegeneration and in vivo ischaemia with- out suppressing synaptic transmission. Br J 7. Whiting, P.J. The GABAA receptor gene fam- ily: New opportunities for drug development.
described studies investigating D3 molecular and pharmacokinetic basis 8. Atack, J.R. Anxioselective compounds acting binding site. Curr Drug Targets CNS Neurol (3 µg/kg). This differential effect cor- drugs—Will they model the next 100? NatRev Drug Discov 2003, 2: 38–51.
10. Duncan, G.E., Moy, S.S., Perez, A., Eddy, Snouwaert, J.N. and Koller, B.H. Deficits in role in CNS research and development.
like to thank the following companies for their 11. Modo, M., Roberts, T.J., Sandhu, J.K. and generous support of this meeting: Eli Lilly, Williams, S.C. In vivo monitoring of cellular GlaxoSmithKline, Merck Sharpe & Dohme, transplants by magnetic resonance imaging achieved blockbuster status (Table I).
1. Alavijeh, M.S. and Palmer, A.M. Effectively meeting the need for long-term neurological 2. Palmer, A.M. Cholinergic therapies for ahead. To meet this need, it will be nec- become more efficient and effective.
3. Walker, M.C., Tong, X., Perry, H., Alavijeh, serum, cerebrospinal fluid and brain extra- cellular fluid pharmacokinetics of lamotrig- ine. Br J Pharmacol 2000, 130: 242–8.
4. Pullar, I.A. and Palmer, A.M. Pharmaco- disorders, the barrier to brain entry (the therapy of neuropathic pain: Progress and geneity in clinical trials, the existence 5. Palmer, A.M. and Carter, N. The role of sodi- 6. Morrison, B., III, Pringle, A.K., McManus, T. et al. L-arginyl-3,4-spermidine is neuro- tion version of a currently marketed upfront and research payments as therapeutic protein. BioGeneriX well as royalties. Under the and Neose will enter into an initial research, license and option agree- 3-month research period. Neose ment, BioGeneriX would have the Neose Technologies and Bio- will receive a payment and supply right to an exclusive, worldwide GeneriX have entered into a supply of protein for research purposes.
and option agreement that, if the During the research period, Bio- license to use Neose’s Glyco- option is exercised, would result in Generix may choose to enter into a PEGylation technology to develop the use of Neose’s proprietary prenegotiated research, license and and commercialize a long-acting, GlycoPEGylationTM technology to option agreement under which next-generation version of the un- develop a long-acting, next-genera- Neose would receive additional disclosed therapeutic protein.
A.M. Palmer and F.A. Stephenson pp. 51–57


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