Mini-Reviews in Medicinal Chemistry, Volume 2, No. 3, 2002
N7-Substituted-5-aryl-pyrrolo[2,3-d]pyrimidines
Represent a Versatile Class of Potent Inhibitors of the Tyrosine Kinase c-Src Pp.201-208
Eva
Altmann, Leo Widler and Martin Missbach
Strategies for Access to Enantiomerically
Pure Ecadotril,Dexecadotril and Fasidotril: A Review Pp.209-217
Thierry
Monteil, Denis Danvy, Miryam Sihel, Richard Leroux and Jean-Christophe
Plaquevent
cycloSal-Pronucleotides – Design of Chemical
Trojan Horses
Pp.219-234
Chris
Meier
Dimeric 4-Aryl-1,4-Dihydropyridines:
Development of a Third Class of Nonpeptidic HIV-1 Protease Inhibitors Pp.235-245
Andreas
Hilgeroth
Recent Advances in the Identification and
Development of 20S Proteasome Inhibitors Pp.247-259
Carlos
García-Echeverría
Cytochrome P450 Retinoic Acid 4-Hydroxylase
Inhibitors: Potential Agents for Cancer Therapy Pp.261-269
V.C.O.
Njar
New Approaches to Raising the HDL Cholesterol
Level
Pp.271-276
Hisashi
Shinkai
Refining Retinoids with Heteroatoms Pp.277-283
D.M.
Benbrook
Phytoecdysteroids Effects on Mammalians,
Isolation and Analysis
Pp.285-293
Mária
Báthori
[Back to top] N7-Substituted-5-aryl-pyrrolo[2,3-d]pyrimidines
Represent a Versatile Class of Potent Inhibitors of the Tyrosine Kinase c-Src
Eva
Altmann, Leo Widler and Martin Missbach
5-Aryl-pyrrolo[2,3-d]pyrimidines
incorporating different N 7 -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.
[Back to top] Strategies for Access to Enantiomerically Pure
Ecadotril,Dexecadotril and Fasidotril: A Review
Thierry
Monteil, Denis Danvy, Miryam Sihel, Richard Leroux and Jean-Christophe
Plaquevent
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 pool
ii- Chemical
resolution of racemic precursors
iii- Enzymatic
resolution and desymmetrization of meso starting materials
iv- 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.
[Back to top] cycloSal-Pronucleotides – Design of Chemical
Trojan Horses
Chris
Meier
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.
[Back to top] Dimeric 4-Aryl-1,4-Dihydropyridines:
Development of a Third Class of Nonpeptidic HIV-1 Protease Inhibitors
Andreas Hilgeroth
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.
[Back to top] Recent Advances in the Identification and
Development of 20S Proteasome Inhibitors
Carlos
García-Echeverría
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 non-specific
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.
[Back to top] Cytochrome P450 Retinoic Acid 4-Hydroxylase
Inhibitors: Potential Agents for Cancer Therapy
V.C.O.
Njar
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. Maj
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.
[Back to top] New Approaches to Raising the HDL Cholesterol
Level
Hisashi
Shinkai
Not only a high
level of low-density lipoprotein (LDL) cholesterol, but also a low level of
high-density 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).
[Back to top] Refining Retinoids with Heteroatoms
D.M.
Benbrook
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 conformationally-restricted 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 ndrastically reduced the toxicity, while retaining
biological activity.Clinical trials of a heteroarotinoid, Tazarotene, confirmed
the improved chemotherapeutic ratio (efficacy/toxicity).
[Back to top] Phytoecdysteroids Effects on Mammalians,
Isolation and Analysis
Mária
Báthori
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.