Current Topics in Medicinal Chemistry - Volume 6, Issue 13, 2006

Inflammation is the natural immune response of the body to infection or other damage, and is vital to survival. However, occasionally the inflammatory response is out of proportion with the tissue damage, and the survival strategy becomes the problem itself. This is the case with many serious chronic and acute diseases, like allergy and asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and septic shock. It is also established that cancerous diseases, atherosclerosis, metabolic disorders like diabetes mellitus and obesity, and CNS disorders such as multiple sclerosis, Alzheimer's disease and stroke, involve important inflammatory components. Even if progress has been made, it is clear that inflammatory conditions at large still represent a formidable therapeutic challenge, and it appears safe to forecast that this will continue to occupy the pharmaceutical industry and those dedicated to drug discovery into the future. On a molecular level, the inflammatory response is highly complex, involving a vast array of messenger molecules interacting with enzymes and receptors of virtually every class, directing recruitment of immune cells to eliminate the source of infection and recover the healthy state. Indeed, absence of inflammation also involves an active immune system and a balance between the inflammatory messengers, which together with the inherent redundancy of the system makes therapeutic intervention a considerable challenge [1]. A recent issue of this journal dealt with new approaches to treatment of inflammatory disorders, and discussed various molecular targets, including synthases, kinases, nuclear receptors, and targets within the intracellular secretory pathway. The G protein-coupled seven-transmembrane receptors, commonly known as GPCRs, heptahelical receptors or 7TM receptors, make up a large family of cell surface receptors which are found on all cell types in the body and are implicated in virtually every physiological process. Comprising about 200 members with known endogenous ligands in addition to numerous sensory and orphan receptors, the 7TM protein superfamily has proven highly suitable as drug targets, with a substantial fraction of all marketed drugs exerting their action through members of this receptor superfamily. The receptors share a number of characteristic features, including an extracellular N-terminal, seven transmembrane α-helical segments, an intracellular Cterminal, and the ability to activate heterotrimeric G proteins. Despite their common architecture, the 7TM receptors act as cell surface receptors for highly diverse endogenous molecules, including large proteins and small peptides, monoamines, nucleosides, and lipids. Inflammatory mediators encompass a corresponding structural diversity, and the contributions in this issue reflect the variety of these messenger molecules as well as the diversity of endogenous 7TM receptor ligands. Chemokines are a family of 8-12 kDa proteins which play a crucial role in directing leukocytes to the site of inflammation through activation of specific 7TM receptors on the cell surfaces. In the first article in this issue, Rosenkilde and Schwartz give an introduction to chemokines and their receptors. They highlight a specific glutamic acid residue in transmembrane segment VII which is highly conserved throughout the chemokine receptor class, but not present in other 7TM receptors, and propose a simplified general chemokine receptor pharmacophore of potential utility for future ligand design where this residue acts as a central anchor point. Representative antagonists for CCR1, CCR2, CCR3 and CCR5 are discussed in light of this hypothesis and related to results from site-directed mutagenesis. In the second article, Purandare and Somerville present the validation of the chemokine receptor CCR4 as target in inflammatory and autoimmune diseases, and the current status of small-molecule CCR4 antagonists. Busch-Petersen concludes the chemokine section by reviewing the currently known classes of antagonists for the interleukin 8 receptors CXCR2 and CXCR1, and the effort to develop these ligands into new antiinflammatory drugs. Only a tenth the size of the chemokines, bradykinin and related small peptides act as pro-inflammatory autacoids through the receptors B1 and B2. Fortin and Marceau review the kallikrein-kinin system, the validation of the two kinin receptors as anti-inflammatory targets, the current status on development of selective peptide and non-peptide modulators of these receptors, and the outlook for developing new drugs from these. Scaling down the size of the messenger molecule by another order of magnitude, histamine is a well-known mediator of allergic and inflammatory responses.........

A majority of small molecule non-peptide ligands for chemokine receptors in general are characterized by the presence of one or two centrally located, positively charged nitrogen atoms and these compounds are also often of relatively similar elongated overall structure with terminal aromatic moieties. In the corresponding main ligand-binding crevice of the chemokine 7TM receptors is found a centrally located glutamic acid residue in position 6 of transmembrane segment VII in 74% of the chemokine receptors but only in approx. 1% of non-chemokine receptors. GluVII:06 has been demonstrated to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule ligands and that the two peripheral chemical moieties of the ligands from this central point in the receptor structure explore each of the two halves of the main ligand binding pocket. It is envisioned that knowledge of this binding mode can be exploited in structurebased discovery and design of novel chemokine receptor ligands and especially ligands with specifically optimized properties.

The chemokine receptor CCR4 is broadly expressed on cells of the immune system. It is known to play a central role in T cell migration to the thymus, and T cell maturation and education. In addition, CCR4 is known to modulate T cell migration to several sites of inflammation in the body, including the skin, and lungs. It is best known as a drug target for airway inflammation and atopic dermatitis, but cells expressing CCR4 are found in many inflammatory diseases. CCR4 small molecule antagonists have not yet reached the clinic, but at least one has been validated in an in vivo model. Here we review the current status of structurally novel CCR4 receptor antagonists.

In the past eight years, numerous series of small molecule CXCR2 and CXCR1 antagonists have been disclosed. These compounds have proved to be effective inhibitors of ELR+ chemokine-induced chemotaxis of neutrophils and other immune cells in vitro and have also been efficacious in several animal models of inflammatory disease. Although some of these compounds have been reported to be in clinical development, no data on clinical studies in patients with inflammatory disease has been revealed to date. This review details the medicinal chemistry and pharmacology of the aforementioned antagonist series.

Kinins are blood-derived local-acting peptides that elicit specific cellular effects via the stimulation of two related G protein coupled receptors. While the B2 receptor subtype, constitutively expressed in various tissues, is believed to mediate most of the physiological actions of kinins in healthy conditions, the B1 receptor, highly regulated during inflammation, has been associated with the sustained actions of these peptides in various pathological situations. Potent peptide and nonpeptide modulators of both kinin receptors have been produced as pharmacological tools and potential therapeutics over the last three decades. More recently, the accumulating evidence suggesting that B1 receptor blockade could be useful for the treatment of pain and inflammatory disorders has led to a shift in drug development efforts toward the synthesis of orally bioavailable nonpeptide B1 receptor antagonists. Nonpeptide ligands of either receptor subtype produced by several industrial organizations often possess significant structural commonalities that can lead to the definition of a pharmacophore, especially when the receptor docking models are compared. The field of kinin receptors ligands research has reached an exciting step of its history, as the near future will reveal whether these molecules are therapeutically beneficial in various human diseases. This review will concisely summarize our current understanding of the biology of kinins and their receptors, before discussing the recent medicinal chemistry developments and challenges that bring new kinin receptor ligands closer to clinical applications.

Antagonists for the Histamine H 1 receptor have been on the market for decades and continue to be successfully used in the treatment of a variety of allergic conditions. The recently discovered histamine H4 receptor subtype is emerging as a new and complementary target for treating inflammatory conditions. In this review, we describe the receptor protein, its putative role in (patho)physiology and the latest ligands that are being developed to explore the feasibility of the H4 receptor as a drug target.

Adenosine receptors belong to the family of G protein-coupled receptors. Four distinct subtypes are known, termed A1, A2A, A2B and A3. Adenosine is an important signaling molecule which is released under inflammatory conditions. It can show antiinflammatory as well as proinflammatory activities, and the contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. Agonists selective for adenosine A1 receptors show antinociceptive activity and are active in animal models of neuropathic and inflammatory pain. Adenosine A2A receptor agonists are potent antiinflammatory drugs. A2A-selective antagonists have shown antihyperalgesic activity in animal models of inflammatory pain. For A2B agonists as well as A2B antagonists antiinflammatory activity has been postulated. Selective A2B antagonists were shown to decrease (inflammatory) pain, and are promising candidates for the treatment of asthma. Adenosine A3 receptor agonists appear to be proinflammatory, while there is evidence for an antiinflammatory effect of A3 antagonists. There are some contradictory findings, and A 3 agonists are being developed for the treatment of inflammatory diseases such as arthritis. Indirect mechanisms increasing the extracellular concentration of adenosine using adenosine kinase inhibitors, adenosine deaminase inhibitors or adenosine uptake inhibitors, or increasing the potency of adenosine at the A1 receptor subtype by allosteric modulators lead to potent antinociceptive and antiinflammatory activity. The advantage of indirectly acting drugs may be their site- and event-specific action since they are only active where adenosine has been released. In the past decade considerable progress has been made towards the identification of novel lead structures and the development of potent and selective ligands for all four adenosine receptor subtypes. A large number of patents has recently been filed and the field is finally in the process of translating many years of basic science into therapeutic application. This review article will focus on compounds published or patented within the past three years.

Habitual cannabis use has been shown to affect the human immune system, and recent advances in endocannabinoid research provide a basis for understanding these immunomodulatory effects. Cell-based experiments or in vivo animal testing suggest that regulation of the endocannabinoid circuitry can impact almost every major function associated with the immune system. These studies were assisted by the development of numerous novel molecules that exert their biological effects through the endocannabinoid system. Several of these compounds were tested for their effects on immune function, and the results suggest therapeutic opportunities for a variety of inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, allergic asthma, and autoimmune diabetes through modulation of the endocannabinoid system.

The involvement of prostaglandin D2 (PGD2) in inflammatory diseases like allergy and asthma is well established, thus blocking the effect of this mediator represents a novel therapeutic approach for the treatment of such diseases. PGD2 is now known to act through two seven-transmembrane (7TM) receptors, DP (DP1) and CRTH2 (DP2), which are also activated by several endogenous metabolites from the arachidonic acid cascade, making the regulatory system highly complex. There has recently been a considerable effort aimed at developing antagonists of the PGD2 receptors for treatment of inflammatory conditions like asthma and rhinitis. Several potent DP antagonists are now known, and one of these is currently in clinical trials for treatment of asthma. CRTH2 has received much attention since its identification as the second high affinity PGD 2 receptor in 2001, and a number of potent and selective antagonists have recently become available. This review will briefly discuss the biological background and validation of DP and CRTH2 as targets for antiinflammatory drugs, and then highlight developments in medicinal chemistry which have appeared in journals and patent applications in the last few years, and which have brought us closer to therapeutic applications of PGD2 receptor antagonists in various indications.