Current Topics in Medicinal Chemistry - Volume 8, Issue 16, 2008

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is a frequent reason for physician consultation, and a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Inflammation is the sequence of events that characterizes the biological response of vascular tissues to harmful stimuli. It is a protective attempt by the body to remove the injurious stimuli as well as initiate the healing process for the tissue. Malfunctions in the processes associated with inflammation comprise a number of disorders which underlie a variety of human diseases There are a number of commonly used drugs available for treatment various conditions of severe pain and inflammation. Opioids, the most powerful of analgesics, are the mainstay for treatment of severe acute and chronic pain. However, opioids have many well-known side effects. Since the isolation of salicylic acid from willow bark almost two hundred years ago, NSAIDs (non-steroidal anti-inflammatory drugs) have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Unlike opioids, NSAIDs do not produce sedation or respiratory depression and have a very low addiction rate. They are, however, not without adverse effects; for example, irritation of the stomach lining. Other anti-inflammatory therapies include steroids, such as glucocorticoids, and new biologics such as TNF-alpha blockers which have had a dramatic effect on many inflammatory conditions. While there is a spectrum of medicinal agents currently available that are indicated as pain and inflammation treatments, they suffer from many limitations. There is a need for the development of better, more efficacious new drugs for these conditions. Researchers are actively working on newer targets that have the potential to selectively interfere with the processes of nociception and inflammation. This special issue of Current Topics in Medicinal Chemistry highlights the some of the state of the art in research aimed at discovering new avenues for treating pain and inflammation. In the first review by Kuduk and Bock, the authors present a case study of the structure-activity relationship and lead optimization efforts made at Merck in targeting the bradykinin B1 receptor with antagonists for treatment of pain. This research has resulted in the identification of a clinical candidate. Reviewing another much-studied target for pain therapy, Broad, Keding and Blanco present an overview of the progress made in development of antagonists of the transient receptor potential vanilloid sub-type 1 (TRPV1), previously vanilloid receptor 1 (VR1). A number of compounds have been evaluated in the clinic for different indications of pain, and this review catalogs the state of the art, along with related pre-clinical data. Fioravanti and Vanderah discuss the pros and cons of antagonizing the opioid receptor like-1 (ORL-1) system in pain therapy. The authors present a systematic review of the published literature that examines the validity of this G-protein coupled receptor of the opioid family as a suitable target for drug candidates. The next review by Pettus and Wurz provides an update on the decade-long effort to develop inhibitors of the p38 mitogenactivated protein (MAP) kinase as anti-inflammatory agents. This review discusses the latest generation of selective p38 inhibitors from different organizations, and the progress towards identifying a small molecule counterpart of current biological anti-inflammatory agents that block TNF-α. Finally, Davis and Xu review the recent progress in developing antagonists of the calcitonin gene-related peptide (CGRP) receptor for treatment of migraine. They present exciting new results that have emerged from clinical evaluation of smallmolecule therapies that validate this target for migraine therapy. Furthermore, large-molecule approaches are also discussed. Pain and inflammation have been the targets of extensive research for the development of new molecular therapeutics. There is a definite unmet medical need for new drugs despite the current availability of multiple treatment approaches in the clinic. This special issue of Current Topics in Medicinal Chemistry presents the progress made in identifying new targets for drugs that address these indications. Some of these targets have now been validated in the clinic; others are being interrogated with new tools in human clinical trials. They represent exciting opportunities afforded by widespread and diligent research by scientists involved in drug discovery that have been documented in these excellent reviews. I would like to thank the authors for taking the time in submitting these highly informative reviews of the current literature. I would also like to thank the chief editor for giving me the opportunity of organizing this effort describing the latest research in this important area. I hope the information presented here is useful in stimulating new ideas and areas of scientific discovery.

Bradykinin B1 receptor antagonists embody a potentially novel approach for the treatment of chronic pain and inflammation. The identification of non-peptide B1 antagonists has been a notable advance in the kinin field that will allow evaluation of their therapeutic potential in the clinical realm. The current review is a high level summary of our contributions to the area that culminated in the discovery of a clinical candidate.

As last year marked the tenth anniversary of the cloning of TRPV1, no attenuation has been observed in the intense interest surrounding this ion channel by both academic labs and pharmaceutical companies alike. Patent searches provide an extensive list of novel TRPV1 antagonists generated within the last 7 years, while literature searches reveal a diverse collection of TRPV1 antagonists that have progressed into pre-clinical in vivo profiling and even clinical development. This review serves to summarize the current knowledge of TRPV1 and TRPV1 antagonists as pain therapeutics and to highlight how use of divergent TRPV1 antagonists is helping to further define the physiological and pathological role of TRPV1 and the scope for TRPV1 antagonist therapies.

Following the cloning of the classical opioid receptors (μ, δ and κ), the opioid receptor like-1 (ORL-1) was identified as a G-protein coupled receptor (GPCR) with 65% structure homology to the other members of the opioid family. Its endogenous ligand nociception/orphanin FQ (N/OFQ) was discovered shortly thereafter, becoming the subject of investigation in numerous studies. Since activation of the ORL-1 receptor by N/OFQ leads to Gαi-coupling and signal transduction similar to that of opioid receptors, N/OFQ was thought to have a role in pain modulation, similar to that of the endogenous opioids. Surprisingly, studies characterizing N/OFQ's effects on pain transmission yielded conflicting results, attributing to N/OFQ both pronociceptive and antinociceptive actions, depending on doses and routes of administration as well as species and sex of the subjects. With the development of selective and potent ORL-1 antagonists, many scientists believed these contradicting actions would be elucidated. Here we review the recent literature reporting the use of novel ORL-1 antagonists, both peptide and non-peptide, in different models of pain and discuss their use as research tools or potential drug candidates.

The p38 mitogen-activated protein (MAP) kinase plays a central role in inflammation. It has been the subject of extensive efforts in both basic research and drug discovery for the treatment of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, where aberrant cytokine signaling is the driver of the disease. This article reviews the patent and journal publication activities during 2006-2008 describing novel small molecule p38α inhibitors.

The critical role of Calcitonin Gene-Related Peptide (CGRP) in migraine has been validated, with two small molecule CGRP antagonists BIBN4096BS and MK-0974 demonstrating efficacy in the reversal of acute migraine attack [1,2]. Multiple approaches have been taken to find the ideal agent that most effectively inhibits CGRP's function. Here, we have summarized the progress made in recent years, including the identification and optimization of an orally bioavailable small molecule CGRP receptor antagonist. We also describe other interventions such as scavenging of CGRP itself. The advantages and disadvantages of these distinct approaches are discussed.

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