Mini-Reviews in Medicinal Chemistry, Volume 4, No. 6, 2004
Contents
Arachidonic Acid Cascade Modulators: The Cyclooxygenase Pathway
Executive
Editors: Jean-Michel Dogne / Xavier de Leval
First and Second Generations of COX-2
Selective Inhibitors Pp.
597-601
Xavier
de Leval, Fabien Julemont, Valerie Benoit, Michel Frederich, Bernard Pirotte
and Jean-Michel Dogne
Structural Approach for COX-2 Inhibition Pp. 603-615
C.
Michaux and C. Charlier
The Second Generation of COX-2 Inhibitors:
Clinical Pharmacological Point of View Pp. 617-624
D.O.
Stichtenoth
COX-2 Selective Inhibitors, Carbonic
Anhydrase Inhibition and Anticancer Properties of Sulfonamides Belonging to
This Class of Pharmacological Agents Pp. 625-632
Claudiu
T. Supuran, Angela Casini, Antonio Mastrolorenzo and Andrea Scozzafava
Recent Development in the Field of Dual COX /
5-LOX Inhibitors Pp. 633-638
Fabien
Julemont, Jean-Michel Dogne, Bernard Pirotte and Xavier de Leval
Advance in Understanding the Biosynthesis of
Prostacyclin and Thromboxane A2 in the Endoplasmic Reticulum
Membrane via the Cyclooxygenase Pathway Pp. 639-647
Ke-He Ruan
New Developments on Thromboxane Modulators Pp. 649-657
Jean-Michel Dogne, Julien Hanson, Xavier de Leval, Bernard Masereel, Philippe Kolh and Bernard Pirotte
Modulation of the Arachidonic Cascade with
ω3 Fatty Acids or Analogues: Potential Therapeutic Benefits Pp. 659-668
Isabelle Roland, Xavier de Leval, Brigitte Evrard, Bernard Pirotte, Jean-Michel Dogne and Luc Delattre
“Dipeptoids”: From the Chemical Structure of
the Endogenous Peptide to the Design of Peptidomimetics Pp. 669-680
Mercedes Martin-Martinez, Rosario Patino-Molina, M. Teresa Garcia-Lopeza and Rosario Gonzalez-Muniza
Predicting Synthetic Accessibility:
Application in Drug Discovery and Development Pp. 681-692
J.C. Baber and M. Feher
The Development of Inhibitors of Heparanase,
a Key Enzyme Involved in Tumour Metastasis, Angiogenesis and Inflammation Pp. 693-702
Abstracts
[Back to top] First and Second Generations of COX-2
Selective Inhibitors
Xavier
de Leval, Fabien Julemont, Valerie Benoit, Michel Frederich, Bernard Pirotte
and Jean-Michel Dogne
The identification
and characterization of the inducible form of cyclooxygenases (COX-2)
stimulated the investigations to develop efficient, non-steroidal
anti-inflammatory drugs (NSAIDs) with reduced side effects (essentially
gastro-intestinal toxicity) compared to classical NSAIDs. This review focuses
on the chemical and pharmacological properties (pre-clinical data) of marketed
COX-2 inhibitors.
[Back to top] Structural Approach for COX-2 Inhibition
C.
Michaux and C. Charlier
The design of
selective COX-2 inhibitors is a new approach to obtain potent,
anti-inflammatory drugs but with less side effects. Several families of such
inhibitors were reported in literature. In this review, the drug design
processes used to understand their binding mode and the origin of selectivity
of these compounds are described.
[Back to top] The Second Generation of COX-2 Inhibitors:
Clinical Pharmacological Point of View
D.O.
Stichtenoth
Valdecoxib,
parecoxib, etoricoxib and lumiracoxib represent the second generation of
selective COX-2 inhibitors. In comparison to the first generation, they show an
at least equivalent efficacy in the treatment of pain and inflammation.
However, the postulated gain of safety is yet difficult to determine and seems
to be, if any, small.
[Back to top] COX-2 Selective Inhibitors, Carbonic
Anhydrase Inhibition and Anticancer Properties of Sulfonamides Belonging to
This Class of Pharmacological Agents
Claudiu T. Supuran, Angela Casini, Antonio Mastrolorenzo and Andrea Scozzafava
The sulfonamides
constitute an important class of drugs, with several types of pharmacological
agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycaemic,
antithyroid, protease inhibitory and anticancer activity among others. A
recently developed class of pharmacological agents incorporating primary
sulfamoyl moieties in their molecule is constituted by the COX-2 selective
inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib.
Another drug of this class, rofecoxib, does not contain sulfonamide moieties,
but the isosteric and isoelectronic methylsulfone group. It was recently shown
that the sulfonamide COX-2 selective inhibitors (but not the methylsulfone
ones) also act as nanomolar inhibitors of several isozymes of the
metallo-enzyme carbonic anhydrase (CA), some of which are strongly involved in
tumourigenesis. In consequence, the potent anticancer effects of the
sulfonamide COX-2 selective inhibitors and the much weaker such effects of
rofecoxib, reported ultimately by many researchers, may be explained by the
contribution of CA inhibition to such processes in addition to COX-2
inhibition.
[Back to top] Recent Development in the Field of Dual COX /
5-LOX Inhibitors
Fabien
Julemont, Jean-Michel Dogne, Bernard Pirotte and Xavier de Leval
Cyclooxygenases
and lipoxygenase are key enzymes in the arachidonic acid metabolism. Dual
inhibitors are drugs able to block both the COX and the 5-LOX metabolic
pathways. Compared to COX or LOX pathways single inhibitors, dual inhibitors
present at least two major advantages. First, dual inhibitors, by acting on the
two major arachidonic acid metabolic pathways, possess a wide range of
anti-inflammatory activities. Secondly, dual inhibitors appear to be almost
exempt from gastric toxicity, which is the most troublesome side effect of
non-selective COX inhibitors.
[Back to top] Advance in Understanding the Biosynthesis of
Prostacyclin and Thromboxane A2 in the Endoplasmic Reticulum
Membrane via the Cyclooxygenase Pathway
Ke-He
Ruan
Recent advances in
topological and structural characterization of the prostacyclin (PGI2)
and thromboxane A2 (TXA2) synthases have led to the
understanding of the biosynthesis of PGI2 and TXA2 at a
structural level. This mini-review focuses on the molecular mechanism of the
isomerization of the prostaglandin H2 to PGI2 and TXA2
by their synthases in the endoplasmic reticulum (ER) membrane coordinated with
cyclooxygenase-1 or -2. This review summarizes the evidences in which the
biosynthesis of PGI2 and TXA2 are influenced/modulated by
the membrane anchor residues of the synthases and the ER membrane itself, and
provides the structural basis for engineering the synthases for the next
generation of gene therapy and drug designs targeting the specific synthases.
[Back to top] New Developments on Thromboxane Modulators
Jean-Michel
Dogne, Julien Hanson, Xavier de Leval, Bernard Masereel, Philippe Kolh and
Bernard Pirotte
Thromboxane A2
(TXA2) is a labile product formed from arachidonic acid by
cyclooxygenase. The pathogenesis of numerous cardiovascular, pulmonary, and
thromboembolic diseases can be related to this metabolite. Therefore, TXA2
modulators have been developed for 20 years. This review will highlight the
evolution in the field of TXA2 modulators.
[Back to top] Modulation of the Arachidonic Cascade with ω3 Fatty Acids or
Analogues: Potential Therapeutic Benefits
Isabelle Roland, Xavier de Leval, Brigitte Evrard, Bernard Pirotte, Jean-Michel Dogne and Luc Delattre
Increasing interest in the role of ω3 fatty acids has arisen in these latest years since evidence of their implication in the cardioprotective fish based diet of the Inuit has been demonstrated. Furthermore, several in vitro, in vivo and epidemiological studies support the benefit of this fatty acids intake in various pathological states such as in the cardiovascular, cancer, inflammation, psychiatric, paediatric, pulmonary, dermatological and ophthalmologic fields. This review will focus on metabolism and pharmacological implication of ω3 fatty acids intake as well as its interest in the prevention or treatment of the above-mentioned pathologies.
[Back to top] “Dipeptoids”: From the Chemical Structure of the Endogenous Peptide to
the Design of Peptidomimetics
Mercedes Martin-Martinez, Rosario Patino-Molina, M. Teresa Garcia-Lopeza and Rosario Gonzalez-Muniza
The present review details the rational multi-step process followed for the discovery of a family of non-peptide CCK receptor ligands (“dipeptoids”), starting from the structure of the endogenous peptide, CCK8. Emphasis will be made on the N- and C-terminal modifications, on the singular effects of the stereochemical changes and the incorporation of conformational constraints into the structure of “dipeptoids”, and on the modifications directed to improve the pharmacological profile of these compounds to afford valuable clinical candidates.
[Back to top] Predicting Synthetic Accessibility: Application in Drug Discovery and
Development
J.C. Baber and M. Feher
The estimation and use of synthetic accessibility in the drug discovery process is discussed. A distinction is drawn between synthetic feasibility and accessibility and the practical uses of an accessibility score are examined. Various techniques used in the estimation of accessibility are described and their utility and potential accuracy compared.
[Back to top] The Development of Inhibitors of Heparanase, a Key Enzyme Involved in
Tumour Metastasis, Angiogenesis and Inflammation
Vito Ferro, Edward Hammond and Jon K. Fairweather
Heparanase is an endo-β-glucuronidase that degrades the glycosaminoglycan heparan sulfate, a major component of the extracellular matrix and basement membranes, and has been implicated in such processes as inflammation, angiogenesis and metastasis. The identification of inhibitors of heparanase is an attractive approach towards developing new therapeutics for metastatic tumours and chronic inflammatory diseases. This review focuses on heparanase inhibitors that have been isolated or synthesised to date. More recent developments in the understanding of heparanase structure and function that may ultimately aid in the future design of inhibitors with improved potency and specificity, are also discussed.