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The multiple receptor systems involved in sleep-wake regulation11 could provide avenues for future research as the biology becomes more fully elucidated. Histamine receptor (H3) antagonists are an active area of research where NCEs have reached clinical evaluation but proof of concept is still required. The orexin pathway has a clear link to the pathophysiology of narcolepsy, and selective OX2 antagonists are being targeted for clinical proof of concept. Drugs that can target the circadian clock mechanisms and related regulatory systems may offer new therapeutic approaches. Drugs targeting receptors for transforming growth factor a (TGFa) and prokineticin are two potential avenues for circadian rhythm modulation.12 Recent studies suggest a role for urotensin II receptors in the regulation of REM sleep through direct activation of cholinergic neurons in the brainstem but it is too early to know whether agents could be identified that could directly target the CNS receptors avoiding the peripheral vasoconstrictive effects mediated by urotensin II.96 Primary Insomnia

Agents that directly target VLPO neuronal projections may represent novel hypnotics. Gaboxadol is a GABAergic agent that affects slow wave sleep and may be beneficial in narcolepsy. Melatonin receptor agonists offer a new perspective on sleep-inducing agents as being more sleep enhancing by virtue of effects on the circadian pacemaker. Circadian Rhythm and Breathing-Related Sleep Disorders

In sleep apnea syndromes, e.g., OSAHS, upper airway restriction leads to deteriorated sleep, ultimately resulting in daytime sleepiness and impaired cognition. Treatments with classical stimulants like amphetamine are limited due to the side effect profile and potential for abuse. Modafinil has been evaluated as adjunctive therapy to CPAP treatment in OSAHS. In a randomized double blind placebo controlled study, modafinil in conjunction with CPAP therapy significantly improved both the subjective and objective measures of daytime sleepiness compared to CPAP alone as assessed on the ESS testing findings supported in a larger study.97 Advances in the treatment of circadian rhythm disorders are still at an early stage as the basic mechanisms and potential drug targets are better understood. Behavioral interventions and light therapy are still the mainstays of circadian disorder therapy.


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Edward R Bacon obtained his PhD degree in organic chemistry in 1980 from the University of Washington (Seattle, WA) under the direction of Prof Niels H Andersen working in the area of sesquiterpene total synthesis. He then moved to the department of Medicinal Chemistry at Sterling Winthrop Research Institute where he worked in a variety of areas including pain, depression, and predominantly in the cardiovascular arena, focusing on congestive heart failure. During this period, he also conducted research in the area of diagnostic contrast media for x-ray/computed tomography (CT) and magnetic resonance imaging (MRI) utilizing nanoparticle drug delivery technology. In 1994 he moved to Nycomed-Amersham where he continued contrast media research including synthesis of targeted radioconjugates for nuclear medicine applications and development of novel devices for cancer brachtherapy. In 2000 he moved to Cephalon, Inc. (West Chester, PA), where currently he is Senior Director, CNS Medicinal Chemistry, and has been engaged in efforts to discover novel agents for the treatment of sleep disorders, neurodegenerative diseases, and oncology.

Sankar Chatterjee obtained his PhD degree in organic chemistry from the Pennsylvania State University (University Park) under the supervision of Prof Maurice Shamma in 1984 working on total synthesis of natural products and study of reaction mechanisms. He then did his postdoctoral research with Prof Steven M Weinreb at the same university in the area of total synthesis of natural product and with Prof Franklin A Davis at Drexel University (Philadelphia, PA) in the area of development of novel synthetic reagents, respectively. In 1987, he joined Franklin Research Center (Philadelphia, PA) to work in the area of parasitic diseases. In 1990, he joined Cephalon, Inc. (West Chester, PA), where he has been involved in the discovery of novel medicinal agents in the areas of neuroscience (wake and cognition promoting agents, stroke, and Alzheimer's disease) and oncology. Currently he holds the title of Associate Director, CNS Medicinal Chemistry.

Michael Williams received his PhD (1974) from the Institute of Psychiatry and his Doctor of Science degree in pharmacology (1987), both from the University of London. Dr Williams has worked in the US-based pharmaceutical industry for 30 years at Merck, Sharp and Dohme Research Laboratories, Nova Pharmaceutical, CIBA-Geigy, and Abbott Laboratories. He retired from the latter in 2000 and after serving as a consultant with various biotechnology/ pharmaceutical companies in the USA and Europe, joined Cephalon, Inc. in West Chester, PA, in 2003 where he is Vice President of Worldwide Discovery Research. He has published some 300 articles, book chapters, and reviews and is Adjunct Professor in the Department of Molecular Pharmacology and Biological Chemistry at the Feinberg School of Medicine, Northwestern University, Chicago, IL.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 139-167

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