Current Topics in Medicinal Chemistry - Volume 6, Issue 2, 2006

Inflammation is an exceedingly complex physiological response involving mixed cellular infiltration into blood vessel walls and surrounding tissues of the affected organ. Neutrophils, macrophages, lymphocytes, and mast cells release cytokines and chemokines that can directly cause tissue damage, enhance local cellular proliferation, provide a chemotactic signal for recruitment of other cells, and upregulate adhesion proteins for promoting the interaction of circulating immune cells with vascular endothelium. Self-limited inflammatory reactions are vital to our resistance to foreign antigens. However, inappropriate inflammatory responses can cause disease, which may take the form of an over-zealous response to foreign antigens, such as allergic reactions, or a response to self-proteins, such as in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. The inflammatory process may begin with an identifiable insult but in the case of chronic inflammatory diseases such as Crohn's the initiating event is usually unknown. The difficulty in treating inflammatory diseases arises from the fact that we are attempting to exert control over a "normal" physiological response. Inherent in this process is that inhibition of the normal albeit over-zealous response implies a similar inhibition of desirable responses mounted by the immune system. Thus, drug development efforts have had to balance the positive effect on the diseased tissue with a negative effect on the rest of the body. Recently however, the pharmaceutical industry has produced enormously successful drugs for treating chronic inflammatory diseases, particularly the therapeutic antibodies such as anti-TNFα, anti-CD20, and other proteins that mimic or inhibit natural intermediates. Despite these successes, however, there is considerable room for improvement in this area, particularly in the development of small molecules. Contained in this issue of CTMC are several papers that highlight recent contributions to the field of anti-inflammatory drug development, including inhibitors of nitric oxide synthase (NOS) and p38 MAP kinase, inhibitors of inflammation associated with coronary artery disease (CAD), and lesser known targets of anti-inflammation such as estrogen receptors, neuropeptide receptors, and the secretory pathway. These contributions should provide invaluable assistance to ongoing NOS and MAPK inhibitor programs, as well as perhaps stimulate the establishment of new approaches to anti-inflammatory drug development. Alan Tinker and Alan Wallace begin by providing a lucid description of the biology and chemistry of NOS, and dissect our current knowledge of the complicated role of the NOS isoforms in inflammation. They then provide a critical and thorough examination of the anti-NOS agents currently under development, providing some recent encouraging results in a field that has had its share of frustration. Charlie Meng makes a convincing argument for atherosclerosis and the attendant CAD as an inflammatory disorder. He provides epidemiological and biochemical evidence to support his assertion that much of the action of statin drugs in CAD is through a reduction of inflammation, which is independent of cholesterol lowering. He concludes by describing a group of principally antioxidant drugs and a more recent generation of multifunctional agents that have shown benefit in treating CAD. Robert Steffan and his group at Wyeth present a novel approach to the treatment of inflammatory disease through an estrogen receptor-mediated inhibition of NF-kB, describing their screening approach and providing in vivo confirmation of the activity of their selective inhibitors. Stefan Laufer and his colleagues Christian Peifer and Gerd Wagner provide an extensive and coherent examination of the recent progress in the development of p38 MAP kinase inhibitors. Their dissection of the SAR of the important structural features of p38 MAPK inhibitors serves as a valuable roadmap for the future development of these important agents. James Waschek together with Catalina Abad and Rosa Gomariz share their invaluable insight into the potential of neuropeptides in the treatment of inflammatory diseases. In outlining the receptors and ligands that comprise the VIP and PACAP systems, they reveal a fertile but largely unexplored system that has the potential to alter the Th1/Th2 cell balance, which has enormous ramifications for the treatment of inflammatory disease. Finally, Jeff Ludwig and I review the functions and potential intervention points within the secretory pathway. This area is vital to normal cellular processes, and harbors thousands of potential targets that can mitigate cellular activation. We provide examples of agents that act on targets within this system, and conclude by summarizing our work with a group of agents that are effective in inflammatory diseases through their action on a target within the Golgi apparatus.

Nitric Oxide (NO) is widely recognized as an important messenger and effector molecule in a variety of biological systems. There is strong evidence from animal models that elevated or lowered NO levels are associated with a variety of pathological states. In nature, NO is synthesised from the amino acid L-arginine by a small family of closely related oxygenase enzymes: the nitric oxide synthases (NOS). A number of studies in animals have associated excessive NO production by one of these enzymes - the inducible NOS isoform (iNOS or NOS-II) - with acute and chronic inflammation in model systems and have also demonstrated that administration of NOS inhibitors can produce beneficial effects. Regrettably, however, the relatively poor potency, selectivity and pharmacokinetic (ADME) profiles of the available inhibitors have so far precluded a convincing demonstration of their efficacy in the clinic. This review will describe the current state of knowledge of the structure and function of NOS and the various approaches that are being followed in the search for truly selective NOS inhibitors as therapeutic agents for inflammatory diseases.

Inflammation has been increasingly recognized as an important player in the pathophysiology of numerous human disorders. Accumulating evidence has led to the conclusion that atherosclerosis is an inflammatory disease, although it was believed to be a disorder of high cholesterol levels in the bloodstream for over a century. Cholesterol does contribute to the pathogenesis of atherosclerosis, but through inflammatory mechanisms. Statins lower cholesterol levels and hence reduce inflammation in the vasculature and prevent heart disease. Statins may also exert anti-inflammatory effects through mechanisms independent of cholesterol lowering. Adhesion molecules, cytokines, oxidative stress, etc. appear to contribute to the inflammatory state of atherosclerosis and therapeutic approaches directed toward these markers or targets have the potential to be effective in reducing inflammation and treating atherosclerosis.

The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-α monoclonal antibody), Adalimumab (recombinant human anti-human TNF-α monoclonal antibody) and Anakinra (recombinant form of human interleukin 1β (IL-1) receptor antagonist) [1-3]. The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1β and TNF-α to be validated targets [4] However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1β and TNF-α signalling network at both the transcriptional and translational level [5, 6]. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-α and IL-1β production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.

Corticosteroids are the mainstay treatment for most severe inflammatory disorders. Due to the considerable toxicity associated with their long-term use, there is a great need for alternative treatments. Recently, two closely related neuropeptides with potent neuromodulatory activities, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have emerged as candidate molecules for the treatment of such pathologies. These peptides act primarily on three high affinity receptor subtypes expressed on multiple immune cell types, and orchestrate a cytokine response that is primarily anti-inflammatory. In this regard, systemic treatment with these peptides has been shown to greatly reduce the clinical symptoms and alter the pathogenic and cytokine profiles in animal models of rheumatoid arthritis, Crohn's disease, septic shock, and multiple sclerosis. Likewise, VIP and PACAP receptor knockout and overexpressing mice show altered immune responses in different models. We review here data demonstrating the potential effectiveness of these peptides in immune disorders, discuss receptor pharmacology and signaling pathways, describe the development of receptor specific agonists and antagonists, and discuss pharmaceutical considerations relevant to the specific delivery of analogs to the appropriate targets.

Inflammatory diseases are a complex group of disorders involving multiple levels of the immune system and as such present a daunting challenge to understand and treat. Contemporary drug development targets individual cytokines, chemokines, and receptors for which we have some knowledge of their function and regulation. One largely unexplored approach is to modify the inflammatory response via targets within the intracellular secretory pathway. This constitutive pathway is responsible for protein processing and trafficking quality control, and is comprised of the endoplasmic reticulum, the Golgi apparatus, and various post-Golgi organelles such as lysosomes, endosomes, secretory granules, and the plasma membrane. Renewed interest in the secretory system has resulted from our expanding appreciation of the role of post-translational processing in protein function, the myriad of inflammatory and other diseases which arise from defects in the secretory system, and the outcome of drug treatments that utilize elements of this pathway to treat human disease. This review will examine the secretory pathway with particular attention to the phenotypes of diseases which result from disruption of its components, as well as the pharmacological agents that utilize the system to modulate aberrant cellular processes.