Current Pharmaceutical Design - Volume 10, Issue 28, 2004

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors (GPCRs), and auxiliary proteins. This pathway has been identified to participate physiologically in numerous biological pathways including energy homeostasis, pigmentation, sexual function, inflammation, cardiovascular function, adrenal function, sebaceous gland lipid production, just to list a few. During this past decade, a clear link between the melanocortin-4 receptor (MC4R) and obesity, in both mice and humans via the regulation of food intake and energy homeostasis, has made this pathway the target of many academic and industrial research endeavors in attempts to develop potent and selective MC4R small molecules as anti-obesity therapeutic agents. Herein, we attempt to summarize the known proteins that constitute the melanocortin system and discuss advances in peptide and non-peptide drug discovery.

Diabetes is a prevalent disease which effects over 150 million people worldwide and there is a great medical need for new therapeutic agents to treat it. Inhibition of protein tyrosine phosphatase 1B (PTP1B) has emerged as a highly validated, attractive target for treatment of not only diabetes but also obesity. Discovery of small-molecule inhibitors has been pursued extensively in both academia and industry and a number of very potent and selective inhibitors have been identified. With X-ray crystallography, the binding interactions of several classes of inhibitors have been elucidated. This has resulted in significant progress in understanding important interactions between inhibitors and specific residues of PTP1B, which could help the design of future inhibitors. However, since the active site of PTP1B that most of these inhibitors bind to is highly hydrophilic, it remains a challenge to identify inhibitors with both excellent in vitro potency and drug-like physiochemical properties which would lead to good in vivo activities.

The peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor superfamily has classically been characterized for its implications in adipocyte differentiation and fat metabolism. Recently, PPARg has been implicated in the pathophysiology of inflammatory and immune responses possibly through inhibition of the mitogen-activated protein kinase (MAPK) pathways or the activation of the transcription nuclear factor kappa B (NF-κB). Thus, these agents might also have therapeutic potential in the treatment of gastrointestinal inflammatory disorders, such as ulcerative colitis and Crohn's disease. The synthetic thiazolidinediones (TZDs), a novel class of insulin-sensitizing drugs, were the first class of compounds identified as PPARγ ligands, and represent a significant advance in anti-diabetic therapy. However, there is less information about endogenous ligands, although the prostaglandin (PG)J2 and the oxidized phosphatidylcholine have been suggested. Furthermore, PPARg ligands have been shown to be potent inhibitors of angiogenesis, a process necessary for tumor growth and metastasis, and protect against cellular transformation. Further work is needed to establish in detail the anti-proliferative and pro-differentiation mechanisms of PPARγ activators and their efficacy in certain cancers.

Thyroid hormones regulate fundamental genes involved in the metabolism, development and homeostasis of vertebrates. The endogenous hormones, L-3, 5, 3'-triiodo-L-thyronine (T3) and L-3, 5, 3', 5'-tetraiodo-L-thyronine (T4), are of limited use in pharmacological intervention, mainly due to cardiovascular liabilities. There exist two subtypes of thyroid hormone receptors (TR), α and β, unequally distributed in the body. As TRα is most abundant in the heart and most effects of thyroid hormones on the heart are mediated through TRα, a reasonable strategy is the development of TR agonists that either are tissue selective or that interact selectively with TRβ. The prospects for the treatment of metabolic diseases with such ligands are considerable and this review describes the massive efforts of the academic and industrial communities during the last decade. It is, however, the author's view that the development of selective ligands only is in its infancy, an opinion highlighted by the limited chemical structural variation of TR ligands as well as the present lack of TR ligands for the treatment of metabolic diseases in clinical phases.

Prostaglandin (PG) D2, the major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases due to its various inflammatory effects. However, the lack of PGD2 (DP) receptor antagonists has limited the study of its essential roles in the disease state. Recent discoveries of several DP receptor antagonists, the development of the mutant mouse and the discovery of a second PGD2 receptor, CRTH2 (chemoattractant receptor-homologousmolecule expressed on Th2 cells) receptor, have revealed the crucial roles of PGD2 and CRTH2 receptors in allergic disorders. This review presents biological evidence that PGD2 plays an essential role in allergy disorders and discusses the therapeutic possibilities of recently reported PGD2 antagonists.

G protein-coupled receptors (GPCRs) can utilize receptor tyrosine kinases (RTKs) to mediate important cellular responses such as proliferation, differentiation and survival. Recent advances in the field suggest that GPCRinduced transactivation of RTKs might be important for diseases such as cancer and cardiac hypertrophy. Depending on the receptor and cell type, GPCR signaling involves activation of several different RTKs. By activating different subsets of RTKs, GPCRs can fine-tune their effects on target cells. Furthermore, RTK-independent signaling pathways also initiated by GPCRs may modify the biological read out of the transactivated RTKs. This review focuses on the mechanisms how GPCRs and intracellular messengers elicit transactivation of different RTKs and the resulting different biological responses.

Chronic obstructive pulmonary disease (COPD) affects over 5% of the adult population and is the only major cause of death in the United States where morbidity and mortality are increasing. Clinically, COPD is characterized by irreversible airflow obstruction and airway inflammation that eventually lead to dyspnea, cough and sputum production. Long-acting β2-agonists (LABAs) are effective in reducing patient symptoms through their bronchodilatory action on airway smooth muscle. More importantly, when LABAs are given in conjunction with inhaled corticosteroids, they appear to provide added benefits for patients. While the mechanisms for this observation are not entirely clear, there is emerging evidence to indicate that LABAs and corticosteroids attenuate different but complementary components of the inflammatory cascade related to COPD. Moreover, LABAs and corticosteroids may beneficially interact to prevent downregulation of β2-receptors in airway cells (and thereby preventing tachyphylaxis) and to facilitate translocation of glucocorticoid receptors into the nucleus of inflammatory cells (thereby, amplifying the anti-inflammatory activity of the corticosteroid). Regardless of the mechanism, several large, high-quality randomized controlled clinical trials indicate that combination therapy of LABA with inhaled corticosteroids improves patient symptoms, and reduces exacerbations by a third (compared to placebo). More importantly, combination therapy produces superior health outcomes than monotherapy with inhaled corticosteroids or LABA, suggesting added clinical benefits of these two compounds in COPD. This article will present a comprehensive overview of the currently available clinical evidence for the use of combination therapy as well as the potential mechanisms of their actions in COPD.

Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both “in vivo” and “in vitro” studies of hypermotility. “In vitro” experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK2 receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.