Current Pharmaceutical Design - Volume 8, Issue 14, 2002

Utilization of fat as a long-term energy storage vehicle is crucial for the maintenance of cellular metabolism and is under intricate and many times redundant control mechanisms. Aberrations in the control of energy metabolism is apparent in diseases such as diabetes and obesity and is evident early on in patients with impaired glucose tolerance. Insulin resistance has been observed at the level of muscle, liver and adipose tissue. Hyperglycemia is the hallmark of diabetes and is characterized by decreased glucose disposal and increased glucose production, driven by enhanced and uncontrolled fatty acid oxidation (FAO). Mechanisms aimed at limiting the availability of substrates or the activity of processes involved in FAO should provide an immediate reduction in undesired glucose production in these individuals. Numerous targets are available which influence directly the metabolism of fat, including limiting availability of substrate to FAO, inhibiting oxidation of the fatty acid per se, and uncoupling the energy obtained during the oxidation of the fatty acid. These include antilipolytic agents which limit the availability of substrate, FAO inhibitors which limit fatty acid transport (carnitine palmitoyl transferase, CoA sequestration), FAO per se (β oxidation), and agents which uncouple the energy of FAO (uncoupling proteins, β3 agonists). These other targets which affect fatty acid metabolism indirectly will be discussed in this review with 184 references.

The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, hepatitis C, and multiple sclerosis. The inflammatory processes leading to tissue damage and disease are mediated in part by the α4 integrins, α4β1 and α4β7, expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands, vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM), expressed in the affected tissue. Upon binding, the combined integrin / CAM interactions at the cell surface result in firm adhesion of the leukocyte to the vessel wall followed by entry into the affected tissue. Elevated cell adhesion molecule (CAM) expression in various organs has been linked with several autoimmune diseases. Monoclonal antibodies specific for α4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The α4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing α4 integrin antagonists have recently appeared. This article discusses the rationale for targeting α4 integrins for the treatment of autoimmune disorders and reviews some currently known antagonists. The methods used to identify lead molecules and the progress of selected antagonists toward becoming new drugs will is also discussed. (131 references).

The phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP, respectively). They are classified into 11 major families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a cAMP-specific enzyme localized in airway smooth muscle cells as well as in immune and inflammatory cells. The PDE4 activity is associated with a wide variety of diseases some of which have been related to an inflammatory state, (e.g. asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA)) while others have recently been connected to autoimmune pathology. Therefore, an intense effort toward the development of PDE4 inhibitors has been generated for the last decade. Unfortunately, the effects of prototype PDE4 inhibitors have been compromised by side effects such as nausea and emesis and the clinical use of those compounds is still limited. Several companies have focused on the design of a new generation of PDE4 inhibitors dissociating beneficial activity and adverse effects. This review highlights the recent data of the most advanced clinical candidates, the design and structure activity relationships of the recent structural series reported in the literature over the last two years, as well as recent advances in the multiple therapeutic indications of PDE4 inhibitors (a review with 375 references).

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine released from T-cells and macrophages, and is a key molecule in inflammation. Although a detailed understanding of the biological functions of MIF has not yet been found, it is known that MIF catalyzes the tautomerization of phenylpyruvate and a nonphysiological molecule, D-dopachrome. A potent tautomerase inhibitor would be expected, as a validation tool, to shed light on role of MIF activity and the relationship between its biological and enzymatic activity. Such tautomerase inhibitors would be useful in the treatment of MIF-related diseases, such as sepsis, acute respiratory distress syndrome (ARDS), asthma, atopic dermatitis, rheumatoid arthritis (RA), nephropathy and tumors. In this review, we have focused on (1) the biological and enzymatic activities of MIF, (2) the discovery of novel, drug-like tautomerase inhibitors of MIF using a structure-based computer-assisted search, and (3) a crystallographic and molecular modeling study of the MIF-tautomerase inhibitor complexes (A review with 133 references).