Chapter 9
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Fragment-Based Drug Discovery for Diseases of the Central Nervous System Vicki L Nienaber* Zenobia Therapeutics, 505 Coast Blvd. South, Suite 111, La Jolla, CA 92037 *E-mail:
[email protected] Although diseases of the central nervous system are among the most devastating to patients and their families, disease modifying treatments have lagged behind other therapeutic areas. Current treatments were primarily discovered by serendipity and address disease symptoms. In the genomic era, understanding of CNS biology and disease associated mutations is growing thereby identifying a new series of putative targets. As CNS biology matures, there is growing need for a discovery paradigm that addresses the unique needs of CNS therapeutics, namely the ability of compounds to cross the blood-brain-barrier. The physiochemical properties of CNS therapeutics have been identified based upon historic data and may be used to guide discovery efforts. One notable variable is that the compounds should be low molecular weight. In this chapter, we discuss the merits of fragment-based lead discovery and how it may be used to address the challenges of CNS drug discovery. We also summarize practical strategies for library design and screening. Finally, we summarize examples of how fragments may be optimized into lead compounds.
Central nervous system (CNS) disorders comprise the second largest area of need in the drug discovery industry behind cardiovascular disease (1). These diseases are among the most devastating for patients. In fact, dementia and psychosis are ranked in the top five most disabling conditions in the world (2). CNS disorders are also among the most expensive for patient care. For example, Alzheimer’s disease which affects over 37 million people worldwide (3) has an © 2011 American Chemical Society In Library Design, Search Methods, and Applications of Fragment-Based Drug Design; Bienstock, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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annual estimated cost to society of >$100 billion in the US alone (4). Despite the undisputed need for treatments and disease modifying therapies for CNS disease, this area has lagged behind other therapeutic areas. In fact, many current treatments were discovered over 50 years ago by serendipity (5). Why is this? It has been attributed to a combination of factors. One confounding factor is the complicated biology and likely multipronged basis for these diseases. Another is the requirement that compounds access the CNS by crossing the blood-brain barrier (BBB). The genomic era has facilitated a new level of understanding of the regulatory processes in cell signaling and biological disorders. Proteins upregulated, downregulated or mutated in disease have been identified. Specifically for CNS disease, efforts such as the Allen Brain Atlas (6) (www.alleninstitute.org) are mapping gene expression in mouse and human brain. In fact, commercial kits such as those available from 23andme (www.23andme.com) are available to the public allowing routine genetic testing for markers of CNS disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), schizophrenia and bipolar disorder. One of these, LRRK2 kinase has a series of activating point mutations associated with increased risk of PD (7–9) and is a popular drug discovery target. Of course, understanding genetic markers for a disease is only the first step, for example, the genetic mutation basis for Huntington’s disease (HD) has been understood since 1993 (10) but it is only recently that targets have been brought forward for development of a therapeutic agent. These targets are being curated and made publically available by the Cure Huntington’s Disease Initiative (CHDI, http://www.hdresearchcrossroads.org/). The Michael J. Fox Foundation also has a significant effort in identification of targets for PD (http://www.michaeljfox.org/) as does the Alzheimer’s Research Forum (http://www.alzgene.org/). These efforts combined with biological validation studies in cells and animals are bringing forward a new generation of targets for CNS drug discovery.
The Blood Brain Barrier: A Unique Consideration for CNS Drug Discovery It is estimated that 98% of potential drug molecules are excluded from the brain (11) which presents a considerable challenge for discovery of CNS therapeutics. For compounds to access the brain, they must cross the blood-brain barrier (BBB) which is formed by endothelial cells of cerebral blood vessels characterized by tight junctions that are present in the brain and at the interface between the blood and cerebro-spinal-fluid (CSF) (12). This barrier maintains cerebral homeostasis and has evolved to protect the brain. Transport systems exist to allow nutrients and amino acids into the brain and efflux transport systems of the ATP binding cassette (ABC) family transport lipophilic molecules, such as xenobiotics, out of the brain. While some CNS penetrable compounds effectively utilize active transport systems to access the brain [e.g. L-dopa for PD], the vast majority of compounds enter the brain by passive diffusion. The efflux transporter most relevant to CNS drug discovery is the P-glycoprotein (P-gp) pump (12). The 180 In Library Design, Search Methods, and Applications of Fragment-Based Drug Design; Bienstock, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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BBB is considered one of the unique challenges in discovery of a successful CNS therapeutic versus other disease areas. Although predictive computational models for compounds that are subject to Pgp efflux are in the early stages of development, general guidelines have been assembled and may be incorporated into the drug discovery process. One such guideline is the “rule-of-four” (13) which states that compounds subject to Pgp transport (Pgp +) will have total hydrogen bond acceptors (N+O) ≥ 8, molecular weight (MW) > 400 and an acidic pKa > 4. Compounds resistant to Pgp transport (Pgp -) will have total hydrogen bond acceptors (N+O) ≤ 4, MW 0. An increased understanding of the physiochemical requirements for brain penetrable compounds provides a unique opportunity in the field of drug discovery both in designing screening libraries and in the lead optimization phase. A defining characteristic for CNS penetrable and Pgp pump resistant compounds is low molecular weight (< 400) indicating that the molecular weight of screening 181 In Library Design, Search Methods, and Applications of Fragment-Based Drug Design; Bienstock, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
compounds should be even less. One may estimate this starting point because it has been shown that lead optimization adds approximately 100 Daltons to the initial hit (23) yielding an upper cut-off of 300 for a CNS screening library. If one uses the average molecular weight of marketed CNS drugs (310), then the desired starting point is even lower at ~200. Screening low-molecular weight scaffolds ( 400
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