Abstract
Diseases of the central nervous system are among the most devastating to patients and their families. Despite this, treatments for these diseases have lagged behind other therapeutic areas. Although social and economic factors may be partly responsible for the paucity of therapeutic agents, a particularly daunting challenge for CNS drug discovery is the need for compounds to cross the blood brain barrier. Recent analyses of successful drugs have shown that their chemical properties have not changed substantially over the past 40 years while the properties of compounds entering the clinic have become inflated. This property inflation has only exacerbated the challenges of CNS drug discovery as the requirements for delivery to the brain are even more stringent than those for other tissues. New approaches are needed to meet these challenges. In this review, 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 compounds discovered by high-throughput screening, substrate evolution and fragment-based lead discovery for well known CNS targets. The results indicate that FBLD may be a key method for discovery of brain penetrable CNS therapeutics.
Keywords: Fragment-based lead discovery, blood brain barrier, central nervous system, Alzheimer's disease, schizophrenia, BACE, GSK3, PDE4
Current Topics in Medicinal Chemistry
Title: Start Small and Stay Small: Minimizing Attrition in the Clinic with a Focus on CNS Therapeutics
Volume: 9 Issue: 18
Author(s): Vicki Nienaber
Affiliation:
Keywords: Fragment-based lead discovery, blood brain barrier, central nervous system, Alzheimer's disease, schizophrenia, BACE, GSK3, PDE4
Abstract: Diseases of the central nervous system are among the most devastating to patients and their families. Despite this, treatments for these diseases have lagged behind other therapeutic areas. Although social and economic factors may be partly responsible for the paucity of therapeutic agents, a particularly daunting challenge for CNS drug discovery is the need for compounds to cross the blood brain barrier. Recent analyses of successful drugs have shown that their chemical properties have not changed substantially over the past 40 years while the properties of compounds entering the clinic have become inflated. This property inflation has only exacerbated the challenges of CNS drug discovery as the requirements for delivery to the brain are even more stringent than those for other tissues. New approaches are needed to meet these challenges. In this review, 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 compounds discovered by high-throughput screening, substrate evolution and fragment-based lead discovery for well known CNS targets. The results indicate that FBLD may be a key method for discovery of brain penetrable CNS therapeutics.
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Cite this article as:
Nienaber Vicki, Start Small and Stay Small: Minimizing Attrition in the Clinic with a Focus on CNS Therapeutics, Current Topics in Medicinal Chemistry 2009; 9 (18) . https://dx.doi.org/10.2174/156802609790102374
DOI https://dx.doi.org/10.2174/156802609790102374 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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