Andreas Reichel

Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept.

Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK).

The Lab Oddity Prevails: Discovery of Pan-Cdk Inhibitor (R)- S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-(Trifluoromethyl)Pyrimidin-2-Yl]Amino}Phenyl)Sulfoximide (Bay 1000394) for the Treatment of Cancer.

Lead optimization of a high‐throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF‐R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose‐limited absorption and high inter‐patient variability, which was attributed to limited aqueous solubility and off‐target activity against carbonic anhydrases. Further lead optimization efforts to address the off‐target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan‐CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.

In Vitro Models of CNS Barriers

This chapter reviews the history and modern applications of isolated preparations of the three main CNS barrier layers and cell culture preparations derived from them. In vitro models give valuable mechanistic information but also provide useful assay systems for drug discovery and delivery programmes. However, it is important to take into account practical issues including species differences and the degree to which the differentiated state of the in vivo barrier is retained. The range of models available is reviewed, with a critical evaluation of their strengths and weaknesses, and guidance in selecting and optimizing a suitable model for particular applications. New understanding of the unstirred water layers and paracellular leak pathway in in vitro preparations gives greater insights into the “intrinsic permeability” of the membrane, and a variety of techniques permit characterization of the transport systems and enzymes contributing to barrier function. Increasingly, aspects of CNS pathology are being modelled in cell culture, aiding the optimization of drug delivery regimes in pathological conditions.

Integrated Approach to Optimizing CNS Penetration in Drug Discovery: From the Old to the New Paradigm and Assessment of Drug–Transporter Interactions

Assessing CNS penetration in drug discovery and development is important for both CNS projects and non-CNS projects that aim to improve desired or to avoid unwanted central effects of their drug candidates. After a brief reasoning on the flawed old concept of maximising total brain levels, the chapter describes the key principles of the new paradigm of examining CNS penetration and distribution by integrating those parameters and processes that are crucial in controlling unbound brain concentrations as surrogate for the pharmacologically active drug concentration in brain. As a consequence, Kp,uu,brain is about to replace the total brain/plasma ratio Kp,brain as measure of the extent of brain penetration. The chapter outlines strategies, methods and approaches both for the optimisation of CNS penetration as well as for avoiding it, including exemplary lead optimisation screening trees of CNS and non-CNS projects. A comprehensive framework is given linking the pharmacokinetics of a compound in the body’s periphery to its central (unbound) exposure and subsequent PKPD relation in animal models of efficacy, including considerations for the translation of the PKPD relationships from rodents to larger animals and human. The chapter furthermore summarises current knowledge of drug–transporter interactions at the level of the BBB, and outlines the potential of the new concept for refueling the fading interest in CNS drug discovery and development as a result of too many clinical trial failures and an insufficient understanding of the reasons.

Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety

The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the prediction of the PK behaviour in human as described herein. The chapter outlines how the level of confidence in the predictions increases with the level of understanding of both the PK and the PK/PD of the new chemical entities (NCE) in relation to the disease hypothesis and the ability to propose safe and efficacious doses and dosing schedules in responsive patient populations. A sound identification of potential drug metabolism and pharmacokinetics (DMPK)-related development risks allows proposing of an effective de-risking strategy for the progression of the project that is able to reduce uncertainties and to increase the probability of success during preclinical and clinical development.

Discovery of new selective glucocorticoid receptor agonist leads

We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.