Current Medicinal Chemistry (v.20, #35)

Chemokines and Chemokine Receptors Blockers as New Drugs for the Treatment of Chronic Obstructive Pulmonary Disease by G. Caramori, A. Di Stefano, P. Casolari, P.A. Kirkham, A. Padovani, K.F. Chung, A. Papi, I.M. Adcock (4317-4349).
Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood; several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti-inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD.

Radiotracers for Molecular Imaging of Cyclooxygenase-2 (COX-2) Enzyme by O. Tietz, A. Marshall, M. Wuest, M. Wang, F. Wuest (4350-4369).
Cyclooxygenase (COX) enzyme is responsible for the formation of important biological mediators including prostaglandins, prostacyclin and thromboxane to trigger many physiological and patho-physiological responses. COXs exist in two distinct isoforms, a constitutively expressed form (COX-1) and an inducible form (COX-2). COX-2 is involved in the body's response to inflammation and pain. Moreover, it has also been shown that COX-2 is overexpressed in many human cancers, and that COX-2 is involved in various neurodegenerative diseases such as Parkinson's and Alzheimer's disease. COX-2 inhibitors are among the most widely used therapeutics for the treatment of chronic and acute pain and inflammation. Non-invasive monitoring of COX-2 functional expression by means of nuclear molecular imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) might provide unique opportunities to obtain data on COX-2 expression levels during disease manifestation and progression to study potential roles of COX-2 under various pathological conditions. The present review summarizes recent research efforts directed to the design and synthesis of radiotracers as molecular probes with special emphasis on COX-2 imaging.

Isoniazid: an Update on the Multiple Mechanisms for a Singular Action by V. Bernardes-Génisson, C. Deraeve, A. Chollet, J. Bernadou, G. Pratviel (4370-4385).
Isoniazid (INH) is one of the most commonly used drugs in treatment of human tuberculosis and the most efficient. Although it has been 60 years since isoniazid was introduced in anti-tubercular therapy and despite the simplicity of its chemical structure (C6H7N3O) with few functional groups, its exact mechanism of action, which could account for its specificity and exceptional potency against Mycobacterium tuberculosis and justify all profiles of INH-resistance, remains elusive and debatable. This complexity can find an explanation in the high reactivity of INH and also in the possibility that multiple targets and pathways could co-exist for this medicinal agent. Indeed, since the discovery of isoniazid's anti-tubercular potency, several propositions for its mode of action have been reported, including its conversion, by a catalase peroxidase within M. tuberculosis, into an active metabolite able, after reaction with NAD, to inhibit an enzyme (InhA) crucial to M. tuberculosis survival. This represents the most consensual mechanism described to date. Nevertheless, none of the proposed mechanisms considered independently can explain the singular and privileged action of the isoniazid structure on the tubercle bacillus, or all the profiles of resistance. The aim of this paper is to reconsider the literature reporting the different modes of action described for isoniazid in the light of the present and most relevant knowledge, with special attention to understanding the molecular mechanistic aspects of the drug's action.

Quinoline-based small molecules have been explored and being developed as anti-inflammatory agents targeting several pharmacological targets namely Phosphodiesterase 4 (PDE4), Transient Receptor Potential Vanilloid 1 (TRPV1), TNF-α converting enzyme (TACE) and Cyclooxygenase (COX). Efforts on Structure Activity Relationship (SAR) studies revealed that the pharmacological activities and target specificities of these quinoline derivatives were mainly dependent on the nature and position of substituent(s) present on the quinoline ring. For example, quinolines having carboxamide moiety displayed TRPV1 antagonism whereas that with carboxylic acid showed COX-inhibition. Similarly, quinolines possessing aniline moiety at C-4, aryl group at C-8 and oxazole ring at C-5 showed PDE4 inhibition. These quinoline derivatives were synthesized by using various synthetic approaches like Pd-mediated C-C (e.g. Suzuki, Sonogashira type coupling etc.) or C-N (the Buchwald-Hartwig type coupling) or C-S bond formation, AlCl3 induced C-C bond formation, traditional amide bond formation or amination, formation of ether linkage or additional heterocyclic rings. All these efforts resulted in the discovery of several quinoline-based anti-inflammatory agents for the potential treatment of acute as well as chronic inflammatory diseases.

Hypothyroidism and Cardiovascular Disease: Factors, Mechanism and Future Perspectives by Anil K. Sharma, R. Arya, R. Mehta, R. Sharma, A.K. Sharma (4411-4418).
Reduced function of the thyroid gland causes Hypothyroidism which is further attributed to defects in the secretion of thyroid hormones triiodothyronine (T3) and tetra-iodothyronine or thyroxine (T4). T3 and T4 hormones are not only known to regulate the rate of metabolism but also affect the growth and rate of function of many other systems in the body such as neuromuscular, gastrointestinal and cardiovascular system. Hypothyroidism patient usually show higher levels of total cholesterol, low-density lipoproteins (LDL), triglycerides, and other lipid molecules associated with heart disease. The question still remained to be addressed though is whether hypothyroidism affects heart and result in cardiovascular disease. The current review updates us with the recent progress in the hypothyroidism area especially in relation to its connecting link with the heart disease. The present study will further enhance our understanding of the intricacies involved in the secretion of thyroid hormones (T3 & T4) and thyroid stimulating hormone (TSH) subsequently affecting serum lipid levels. The study may help to dice-out cardiovascular risk factors associated with hypothyroidism so that effective measures could be taken prior to occurrence of coronary heart disease.

A peptide microarray fabricated on a non-fouling phosphatidylcholine-polymer-coated surface for a high-fidelity analysis of a cellular kinome by H. Ikeda, J. Kamimoto, T. Yamamoto, A. Hata, Y. Otsubo, T. Niidome, M. Fukushima, T. Mori, Y. Katayama (4419-4425).
Phosphatidylcholine-polymer-coated plastic slides were utilized for the fabrication of peptide microarrays for cellular kinome analysis. According to the non-fouling features of the surface, the signal-to-noise ratio of the detection of phosphorylated peptides improved by about 100-fold from that of a peptide microarray fabricated on a glass slide blocked by a commercial BSA-based reagent. When the phosphatidylcholine-polymer-coated peptide microarray was applied to the analysis of the kinome of HCC827 cells, hyperactivation of c-Src and EGFR were successfully detected.

Molecular Effects of Diphenyl Diselenide on Cholesterol and Glucose Cell Metabolism by J.T. da Rocha, L. Trapani, M. Segatto, P. La Rosa, C.W. Nogueira, G. Zeni, V. Pallottini (4426-4434).
This study was designed to investigate the molecular effects of diphenyl diselenide ((PhSe)2) on cholesterolmetabolism in HepG2 cell line in a dose-dependent manner. The protein levels of both total and phosphorylated 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR and P-HMGR), low-density lipoprotein receptors (LDLr) andthe proteins involved in their regulatory network were analyzed by Western blotting, and the effect of (PhSe)2 on HMGRactivity was measured. Additionally, we also evaluated the effects of this compound on glucose transporter type 4(GLUT4) translocation using fluorescence microscopy in L6 skeletal muscle cell line.;Results demonstrated that (PhSe)2 increased P-HMGR, HMGR, and LDLr protein levels as well as simvastatin treatment,which was used as positive control, without directly affecting HMGR activity. We observed that both long- and short-termHMGR regulation mechanisms are involved in the effects of (PhSe)2, as this compound was able to augment Sterol regulatoryelement binding proteins (SREBP)-1 and Insulin induced gene (Insig)1 protein levels, and to increase AMP activatedkinase (AMPK) activation state. We also found that, in L6 skeletal myotubes, 10 μM (PhSe)2 increases GLUT4translocation through AMPK activation.;Taken together, these findings suggest that (PhSe)2 can modulate the expression of some proteins involved in cholesteroland glucose cell metabolism.