Process of Drug Discovery
The process of drug discovery encompasses a period of intense R&D effort that involves: 1) search for a target to start a program or project, 2) lead generation and optimization steps to allow candidate drug selection, 3) human testing to achieve proofs of mechanism, principle, and concept, hopefully leading to regulatory approval. This process can be classified simply in terms of target identification and target validation. Target identification is to explore the connection between the manipulations of a target to intended clinical actions. The choice of a novel target often depends on clinical values. Target validation always includes appropriate pharmacology, acceptable therapeutic index in preclinical models, and subsequent validation in clinical settings.
Challenges in Central Nervous System (CNS) Drug Discovery
CNS disorders are one of the greatest areas of unmet medical need with a large societal burden and healthcare impact. Unfortunately, few CNS drug approvals have succeeded over the past two decades, leading many pharmaceutical companies to deprioritize this area. There are many challenges along the way to the approval of new drugs to treat CNS disease. The reasons for the failures are likely to be multifactorial.
-
The complexity of brain anatomy and function
The CNS is separated from the blood by blood-brain barrier (BBB) and other barriers, which has a huge impact on the relationship between plasma PK and neuro-PK. Moreover, the CNS is far from being a homogenous tissue. It has many different tissue structures and fluid cavities, while target expression may variate substantially among the different locations and, also, the same target may have distinct functions in different locations. Besides, there is fluid flow, including cerebrospinal fluid (CSF) and extracellular fluid (ECF). Furthermore, CNS contains lymphatic vessels, thus also lymph flow needs to be taken into account. All these processes have an impact on neuro-PK. Last but not least, neuro-PD is typically not directly quantifiable and needs to be assessed indirectly, using biomarkers that may be more or less adequate in reflecting the real CNS effect. Thus, due to this reason, it is difficult to measure and predict neuro-PD.
-
The inaccessibility of the human brain for sampling
Effective and cost-efficient tools are important for pharmaceutical companies to measure human brain target site exposure before moving forward to more expensive clinical trials. However, the possibility of direct measurement is highly limited. Therefore, CNS drug distribution in the human brain cannot be obtained directly but must be inferred from in silico, in vitro, and in vivo preclinical experimental approaches.
-
Inadequate knowledge on neuro-PK
Neuro-PK results from transport across the BBB and blood-cerebrospinal fluid barrier (BCSFB), intra-brain distribution, and target interaction. The free drug hypothesis stating that the unbound drug concentration is available for membrane transport and target interaction has been around for many years. However, in CNS drug discovery, the measurement of unbound drug concentrations is typically not applied, not just due to the lack of quick and easy assay methods, but also due to a lack of understanding of the drivers in neuro-PK processes.
CNS diseases are typically multifactorial and complex. They are characterized by genetic, physiological, neurochemical, degenerative, and inflammatory components, which display variation within the patient group. Moreover, CNS diseases often get diagnosed in a late stage of the disease, where the chance of curing the disease is virtually zero, where at best disease progression can be halted, and often symptom suppression is the only possibility left. All these make it very difficult to define a CNS disease, and its state and stage.
-
Problems in target identification and validation
Target validation aims to determine whether a biological compound is directly involved in the disease of interest and whether it can be modified by a drug or other interventions. However, to date, no successful therapeutic approach has been demonstrated based on this knowledge, indicating that a valid target does not per se guarantee the development of a drug. Moreover, in many cases, the etiology of CNS diseases is multifactorial, making target identification and validation difficult.
Over the past two decades, CNS drug discovery has been relatively unsuccessful in delivering new therapeutics for psychiatric and neurological disorders. However, the need for novel therapies for CNS disorders with improved efficacy, safety, and tolerability has never been in question. With top-class scientific experts and state-of-the-art technologies as well as substantial experience and expertise in drug development, Creative Biolabs provides comprehensive services for psychotropic drug development. We offer high-quality systematic analysis of CNS transport services to facilitate the research and development of CNS drugs. Please contact us for more information and a detailed quote.
For Research Use Only.
