Mini Reviews in Medicinal Chemistry - Volume 2, Issue 3, 2002

5-Aryl-pyrrolo[2,3-d]pyrimidines incorporating different N7-substituents have been prepared and evaluated for their inhibitory potency towards the tyrosine kinase c-Src. Optimization of these compounds resulted in highly potent c-Src inhibitors, some (e.g. 4g, 6g, 7h, 8l ) with excellent specificity towards other receptor and nonreceptor tyrosine kinases. In addition compounds 4g, 5b and 5c are characterized by a good pharmacokinetic profile.

Ecadotril and dexecadotril are powerful and selective inhibitors of neprilysin (NEP, EC 3.4.24.11) and are being developed as therapeutic agents, since they behave as prodrugs of the enantiomers of thiorphan. They exhibit different pharmaceutical profiles (intestinal antisecretatory action for the (R) enantiomer, i.e. dexecadotril, and cardiovascular activity for the (S) enantiomer, i.e. ecadotril). Fasidotril is a related compound which has special interest as an equipotent dual inhibitor of NEP and ACE (EC 3.4.15.1). This behavior confers on fasidotril powerful pharmaceutical properties in the cardiovascular field. This review deals with various synthetic approaches, either published or patented, for access to the enantiomerically pure or highly enriched forms of these drugs. Thus, different methods have been studied, which are taken from different methodologies of resolution procedures and asymmetric synthesis, namely :i- Synthesis from a chiron from the chiral poolii- Chemical resolution of racemic precursorsiii- Enzymatic resolution and desymmetrization of meso starting materialsiv- Asymmetric synthesis, including enantioselective catalytic hydrogenation, alkaloid catalyzed asymmetric Michael additions, and diastereoselective alkylation of a chiral derivative.Some of these methods are used in industrial processes leading to the indicated compounds.

Pronucleotides represent a promising alternative to improve the biological activity of nucleoside analogues against different viral diseases. The basic idea is to achieve nucleotide delivery into cells bypassing limitations encountered during the intracellular formation of nucleotides. The cycloSal-concept is one of several pronucleotide systems reported so far. For some nucleoside analogues, the cycloSal-approach improved antiviral potency thus broadening the applicability of nucleosides. The initial design, chemistry, the proof-of-principle and different applications of the cycloSal-strategy will be discussed in this review.

Cross-resistance development against most peptidic HIV-1 protease inhibitors (PI) forces the development of nonpeptidic alternatives. The classes of nonpeptidic protease inhibitors was limited so far to cyclic ureas and 4-hydroxy-2-pyrones with problems of limited bioavailability by extensive metabolism and protein binding. Cage dimeric 4-aryl-1,4-dihydropyridines have been developed as third class of nonpeptidic PIs. In the following synthesis, molecular modeling and biological activities of a first series of the novel PIs are reviewed. Bioavailability of the dimers will not be limited by protein binding and metabolism as far as evaluated.

The involvement of the 20S proteasome in the degradation of critical intracellular regulatory proteins has suggested the potential use of proteasome inhibitors as novel anti-inflammatory agents and for the treatment of cancer and auto-immune diseases. Early inhibitors of the 20S proteasome were relatively nonspecific compounds and used for in vitro studies of the ubiquitin / proteasome-dependent degradation pathway. The inherent drawbacks of these inhibitors (e.g., non-target specific, too reactive or unstable) has prompted medicinal chemists to search for alternative subunit-specific proteasome inhibitors. This manuscript summarises recent salient medicinal chemistry achievements in this area of research.

Retinoids play a crucial role in cellular differentiation and proliferation of epithelial tissue and their utility in oncology and dermatology is well documented. This mini review focuses on the role of all-trans-retinoic acid (ATRA or RA), the principal endogenous retinoid and its metabolism in cancer therapy.ATRA has been used successfully in differentiating therapy of acute promyelecytic leukemia and other types of cancers. However, its usefulness is limited by the rapid emergence of ATRA resistance due (in part) to ATRA - induced acceleration of ATRA metabolism. A novel strategy to subjugate the limitation associated with exogenous ATRA therapy has been to modulate and / or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzyme(s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis and evaluation of RAMBAs since 1987. Major emphasis is given to liarozole, the most studied and only RAMBA to undergo clinical investigation and also the recently developed novel and highly potent 4-azoly retinoids. The potential role of a new family of cytochrome P450 enzymes, CYP26, with specificity towards ATRA is also discussed.

Not only a high level of low-density lipoprotein (LDL) cholesterol, but also a low level of highdensity lipoprotein (HDL) cholesterol, is a critical risk factor for atherosclerosis and coronary heart disease. Although fibrates and niacin can be used to improve low HDL cholesterol levels, their effect is not wholly satisfactory, so better drugs for the elevation of HDL cholesterol are desired. Among the many methods that may be used to raise HDL cholesterol levels, this review focuses on inhibitors of cholesteryl ester transfer protein (CETP) and on nuclear orphan receptor agonists that mediate the expression of ATP-binding cassette transporter 1 (ABC1).

Retinoids are a group of synthetic compounds designed to refine the numerous biological activities of retinoic acid into pharmaceuticals for several diseases, including cancer. Designs that conformationallyrestricted the rotation of the structures resulted in arotinoids that were biologically active, but with increased toxicity. Incorporation of a heteroatom in one cyclic ring of the arotinoid structures drastically reduced the toxicity, while retaining biological activity. Clinical trials of a heteroarotinoid, Tazarotene, confirmed the improved chemotherapeutic ratio (efficacy / toxicity).

Ecdysteroids are known insect moulting hormones, regulating the insects'metamorphosis. At the same time, ecdysteroids reveal beneficial effects on humans and animals alike. Medicinal plants have been subjected to an intensive research, addressing the presence of ecdysteroids. The possible utilization of medicinal plant deals with their use as raw materials for health preparations and also for the isolation of new phytoecdysteroids.Research on the plant ecdysteroids involves two basic lines. Isolation of major compounds and scout their physiological effects, and isolation of minor ecdysteroids to find new compounds.This review summarizes the recent efforts in the ecdysteroid research including their indication as health improvement preparations, chromatography of ecdysteroids and certain methods for identification of new ecdysteroids.