Current Topics in Medicinal Chemistry - Volume 11, Issue 6, 2011

As guest editors of this thematic issue of Current Topics in Medicinal Chemistry focusing on “Deorphanized GPCRs in Medicinal Chemistry and Drug Discovery” we would like to thank all the contributors for their support and the submission of excellent articles to important key aspects of GPCR-research. Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve Gproteins and their receptors the so called G-protein coupled receptors (GPCRs). These receptors consist of 7 trans-membrane helices and the extracellular N-terminal loop as well as the intracellular C-terminal loop being responsible for the interaction with the G-proteins. The active site where binding to the endogenous ligand as well as to exogenous agonists or antagonists takes place, is located in the membrane and is geometrically designed by few specific features of the trans-membrane helices. The collection of reviews starts with an insightful survey of the role of corticotropin-releasing factor (CRF) in depression and other mood disorders. After a description of the molecular and anatomical elements of the corticotropin releasing hormone system, Nemeroff and colleagues revisit the discovery story of this intriguing system and summarize the current knowledge of the role of this GPCR-binding molecule in depression, early life stress and the sustained impact of early life stress on the CRF system as a whole. They finish with a review of our current understanding of the function of the receptor system, which analyzes gain- or loss-of function studies and ends with current pharmacological attempts and trials to modulate the disease pathology of depression, anxiety and other stress response. It then goes on with an article on three orphan GPCRs which are structurally related with a putative function in inflammation, EBI2, GPR18 and GPR17. The group of Rosenkilde et al. has been intimately involved in the discovery and initial characterization of these three receptors and lay out the current, still fragmented and sometimes controversial, status of our knowledge on these receptors. While there is currently no pharmacological tool-compound to target the receptors, the authors provide the evidence for a rationale why a drug development program might be fruitful. The third review by Serhan and colleagues introduces the reader to a fairly new and as yet pharmacologically little explored concept of “resolution of inflammation”. Rather than assuming that the inflammatory process simply wanes-off with time the authors have been identifying active resolution signaling mechanisms mediated by lipid-binding GPCRs. This whole new and fascinating arena of “resolution pharmacology” is exemplified with three GPCR families, those binding Lipoxins, those binding Resolvins and the so far least characterized protectins. The article integrates both an authoritative overview and an insight into the first-hand discovery story of these receptor systems. Article number 4 by Lindsley et al. summarizes and evaluates recent efforts in the field of histamine H3 receptor antagonists and inverse agonists and discusses potential therapeutic uses of such compounds for the treatment of pathologies involving neurotransmitters. The article as well summarizes the medicinal chemistry status in this important field of pharmaceutical research. The subsequent article by Leurs et al. reflects the aspect of histamine H4 receptor agonism and antagonism and describes the successful design of selective H4 receptor agonists as well as antagonists, the efforts to analyze receptor ligand interactions with site directed mutagenesis experiments and gives an insight into structure-activity- relationship data of different chemical classes of receptor ligands. The following article written by Rocher et al. abstracts the recent efforts to find negative allosteric modulators of the metabotropic glutamate receptor 5 and delineates the potential of these agents for the treatment of CNS (anxiety, depression or neurodegeneration) as well as non-CNS disorders with a focus on gastro-esophageal acid reflux disease. Rocher et al. deliver a comprehensive summary over the most important medicinal chemistry efforts within this domain of potentially therapeutically useful molecules. The next article by Coleman et al. concentrates mainly on Merck's efforts towards the identification of potent dual orexin-1 / orexin-2 receptor antagonists for the treatment of diverse aspects of sleep disorders focusing on primary insomnia. The article is an excellent summary of a significant amount of medicinal chemistry work and gives a very interesting insight into strategies to design and optimize dual orexin receptor antagonists. The last article of this thematic volume by Bolli and co-workers is an extensive and insightful review of the current landscape of the discovery and development of Sphingosine-1-phosphate (S1P) receptor agonists, which have received a lot of attention recently as a nonselective S1P receptor agonist developed by Novartis (FTY720) is likely to become the first oral treatment for multiple sclerosis. As a consequence, the review focuses on agonists for the receptor S1P1, the target responsible for the reduction of blood lymphocyte count and therefore for efficacy in autoimmune disease. After an introduction to the biology of S1P itself, the remainder of the article concentrates on the medicinal chemistry efforts targeting S1P1, that have been described either in peer-reviewed publications or in the patent literature. Truly, a who-is-who of the S1P1 agonist field. It was a very interesting if not exciting endeavor to put this thematic issue of “Current Topics in Medicinal Chemistry” together. The result is of excellent quality due to the very important contributions of all the authors. We are convinced that to contribute to the field of GPCR-research is of key importance for the pharmaceutical community to deliver efficacious and safe treatments for severe diseases in the near future.

Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research focused on delineating the function of the hypothalamicpituitary- adrenal (HPA) axis and subsequently examined its role in mediating the mammalian stress responses and its hyperactivity in depression. Much evidence now supports an important function of the biological mediators of this system in relation to not only depression, but also anxiety, substance abuse, and psychotic disorders, and implicates several components of this system as areas of intervention for novel pharmacotherapy. Perhaps the best studied central nervous system (CNS) component of this system is corticotropin-releasing factor (CRF), and considerable research has focused on its role in the HPA axis, as well in extrahypothalamic brain regions.

7TM receptors constitute one of the largest superfamilies of proteins in the human genome. They are involved in a large number of physiological and pathological processes and thus represent major and important drug targets for the pharmaceutical industry. Although the majority have been deorphanized, many remain orphan and these orphan receptors constitute a large pool of potential drug targets. This review focuses on one of these orphan targets, the Epstein-Barr Virus- induced receptor 2, EBI2 (or GPR183), together with two structurally related receptors, GPR17 and GPR18. The pharmacology and “druggability” of these three receptors are reviewed through a thorough description of their structural and functional properties and in vivo biology together with a status of currently available ligands for these receptors.

Resolution of inflammation, an actively coordinated program, is essential to maintain host health. It involves effective removal of inflammatory stimuli and the spatio-temporal control of leukocyte trafficking as well as chemical mediator generation. During the active resolution process, new classes of small, local acting endogenous autacoids, namely the lipoxins, D and E series resolvins, (neuro)protectins, and maresins have been identified. These specialized proresolving lipid mediators (SPM) prevent excessive inflammation and promote removal of microbes and apoptotic cells, thereby expediting resolution and return to tissue homeostasis. As part of their molecular mechanism, SPM exert their potent actions via activating specific pro-resolving G-protein coupled receptors. Together these SPM and their receptors provide new concepts and opportunities for therapeutics, namely promoting active resolution as opposed to the conventionally used enzyme inhibitors and receptor antagonists. This approach may offer new targets suitable for drug design for treating inflammation related diseases, for the new terrain of resolution pharmacology.

This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H3 antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H3 ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H3 ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H3R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H3R antagonists/inverse agonists.

The deorphanization of the histamine H4 receptor (H4R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H1, H2 and H3 receptor ligands were found to have significant affinity for H4R, several agonists and antagonists with high affinity for H4R and selectivity over the other histamine receptors were successfully designed and synthesized. Moreover, site-directed mutation studies on H4R have been performed and reveal detailed information on receptor-ligand interactions. This review will focus on the most important H4R ligand scaffolds and their structure-activity relationships and selectivity over other histamine receptors and specific H4R functional activity. Experimental data are used to construct and validate high resolution three-dimensional receptor-ligand models and, vice versa, in silico models are used to design and rationalize experimental studies to probe receptor-ligand interactions.

Allosteric modulators of metabotropic glutamate receptors (mGluRs) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.

Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity.

Sphingosine 1-phosphate (S1P) evokes a plethora of physiological responses by stimulating members of a G protein-coupled receptor family, known as S1P receptors. Currently five different mammalian S1P receptor subtypes, S1P1-5, each with a different cellular expression pattern, were identified. The S1P1 receptor in particular has attracted major interest throughout the pharmaceutical industry following the breakthrough discovery that this S1P receptor subtype is critically involved in the regulation of lymphocyte trafficking through secondary lymphoid organs. Since then, examples of synthetic S1P1 agonists with lymphocyte reducing and immunomodulating activity demonstrated efficacy in numerous preclinical models of autoimmune disease and transplantation. Notably FTY720 (fingolimod), a pro-drug that is phosphorylated in vivo and converted into a non-selective S1P1,3,4,5 receptor agonist, has been widely used to increase the understanding of S1P1 receptor biology. Results from recently completed phase III clinical trials using FTY720 paved the way for this non-selective S1P1 receptor agonist to become the first oral therapy in multiple sclerosis, with potential expansion into many other autoimmune diseases. This review briefly outlines the field of S1P1 receptor biology and summarizes recent approaches in medicinal chemistry to discover potent and selective S1P1 receptor agonists. In particular, the complexity of discovering a molecule akin to FTY720 but with an improved side-effect profile will be discussed.