Mini-Reviews in Medicinal Chemistry, Volume 4, No. 9, 2004
Contents
Histamine
Receptors
Executive
Editors: Rob Leurs / Henk Timmerman
Dual Acting Antihistaminergic Agents Pp.923-933
R.T.
Scannell, E. Differding and P. Talaga
Structure-Activity Relationships of Histamine
H1-Receptor Agonists Pp.935-940
Heinz
H. Pertz, Sigurd Elz and Walter Schunack
Structure-Activity Relationships of Histamine
H2 Receptor Ligands Pp.941-954
Stefan
Dove, Sigurd Elz, Roland Seifert and Armin Buschauer
Histamine H3 Receptor Agonists Pp.955-963
I.J.P.
De Esch and K.J. Belzar
Medicinal Chemical and Pharmacological
Aspects of Imidazole-Containing Histamine H3 Receptor Antagonists Pp.965-977
Holger
Stark, Markus Kathmann, Eberhard Schlicker, Walter Schunack, Birgit Schlegel
and Wolfgang Sippl
Medicinal Chemistry and Biological Properties
of Non-Imidazole Histamine H3 Antagonists Pp.979-992
Marlon
Cowart, Robert Altenbach, Lawrence Black, Ramin Faghih, Chen Zhao and Arthur A.
Hancock
The Histamine H4 Receptor and
Potential Therapeutic Uses for H4 Ligands Pp.993-1000
Jill
A. Jablonowski, Nicholas I. Carruthers and Robin L. Thurmond
General Review
Recent Advances in the Medicinal Chemistry of
a-Aminoboronic Acids, Amine-Carboxyboranes and
Their Derivatives Pp.1001-1018
Valery
M. Dembitsky, Abed Al Aziz Quntar and Morris Srebnik
Abstracts
[Back to top] Dual Acting Antihistaminergic Agents
R.T.
Scannell, E. Differding and P. Talaga
Histamine is a
primary mediator in allergic response and acts in concert with other agents to
impact disease progression. Respiratory disorders such as asthma, rhinitis and
dermatological conditions such as urticaria involve histamine along with other
mediators. An antihistamine that possesses an additional property of
counteracting the effects mediated by these other mediators should offer some
therapeutic benefit over a selective antihistaminergic agent.
[Back to top] Structure-Activity Relationships of Histamine
H1-Receptor Agonists
Heinz
H. Pertz, Sigurd Elz and Walter Schunack
Significant progress
in the development of potent and selective histamine H1-receptor
agonists has been achieved since 1990. Optimisation of the class of
2-phenylhistamines has furnished 2-[3-(trifluoromethyl)phenyl]histamine and its
Na-methyl derivative. The discovery of histaprodifen
(2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) and the novel
lead compound suprahistaprodifen (Na-2-[(1H-imidazol-4-yl)ethyl]histaprodifen)
represents additional milestones in the H1-receptor agonist field.
[Back to top] Structure-Activity Relationships of Histamine
H2 Receptor Ligands+
Recent research on
histamine H2 receptor agonists was focused on quantitative
structure-activity relationships and receptor models explaining the activity of
imidazolylpropylguanidines. Their selectivity for guinea pig vs. human isoforms
was investigated using H2 receptor-Gsa fusion proteins and attributed to amino acid
differences in transmembrane domains 1 and 7. New antagonists result from
approaches to improve pharmacokinetic properties and to design hybrid drugs
which additionally have gastroprotective or anti H. pylori
activity.
[Back to top] Histamine H3 Receptor Agonists
I.J.P. De Esch and K.J. Belzar
The SAR of H3
ligands has been difficult to evaluate because of species differences, multiple
isoforms and constitutive activity, among other complicating factors. A review
is given of the sometimesconflicting affinity, activity and efficacy data of H3
agonists that has been described in literature to date.
[Back to top] Medicinal Chemical and Pharmacological
Aspects of Imidazole-Containing Histamine H3 Receptor Antagonists
Holger
Stark, Markus Kathmann, Eberhard Schlicker, Walter Schunack, Birgit Schlegel
and Wolfgang Sippl
The first
antagonists known for the histamine H3 receptor were
mono-substituted imidazolecontaining compounds like thioperamide. Meanwhile
numerous novel leads have been developed possessing improved affinities,
selectivities, specificities, and pharmacokinetic properties. Scope and
limitations of this promising class are discussed concerning their
structure-activity relationships as well as pharmacological and potential
therapeutic aspects.
[Back to top] Medicinal Chemistry and Biological Properties
of Non-Imidazole Histamine H3 Antagonists
Marlon
Cowart, Robert Altenbach, Lawrence Black, Ramin Faghih, Chen Zhao and Arthur A.
Hancock
The H3
receptor is prominently expressed in neuronal tissues, and H3
antagonists have been proposed as drugs with benefits in disorders of
cognition, attention, pain, allergic rhinitis, and obesity. The
structure-activity relationships (SAR) of various classes of non-imidazole H3
antagonists are reviewed, along with highlights of functional efficacy in
tissue-based and animal disease models.
[Back to top] The Histamine H4 Receptor and Potential Therapeutic Uses for
H4 Ligands
Jill
A. Jablonowski, Nicholas I. Carruthers and Robin L. Thurmond
Histamine is a
biogenic amine that plays a host of physiological roles and the three major
functions for histamine have been largely defined by the activity of three
receptors. The inflammatory wheal and flare response is driven by the H1
receptor [1]. The H2 receptor controls gastric acid secretion in the
gut [2]. The H3 receptor is involved in neurotransmitter release in
the central nervous system [3]. The recent discovery of the histamine H4
receptor by several groups has lead to the re-evaluation of the physiological
role for histamine.
[Back to top] Recent Advances in the Medicinal Chemistry of
a-Aminoboronic Acids, Amine-Carboxyboranes and
Their Derivatives
Valery
M. Dembitsky, Abed Al Aziz Quntar and Morris Srebnik
This article
describes recent developments in the synthesis and biological activity of a-aminoboronic acids, amine-carboxyboranes and
their derivatives as potential therapeutic agents. a-Amino acid analogues are of considerable
interest as inhibitors of enzymes involved in amino acid and peptide
metabolism. In particular, α-amino alkylphosphonic acids and a-amino alkylboronic acids, in which the
carboxyl group of amino acids is replaced by a phosphonic acid or boronic acid
function, respectively, constitute a unique class of amino acid mimics from
which a number of potent enzyme inhibitors have been synthesized. The
inhibitory activity mainly stems from the fact that the tetrahedral phosphonic
moiety or the tetrahedral adduct of electrophilic boronic acid is a good mimic
of the putative tetrahedral transition state or intermediate encountered in the
enzymatic hydrolysis or formation of peptides. Since the peptide hydrolysis and
formation invariably involves the tetrahedral high energy species in the course
of the reaction, these amino acid mimics serve as a general key element for
inhibitors of a broad spectrum of proteases and peptide ligases. Serine
protease inhibitors provide promising compounds having a P site binding moiety
and a boronic acid chelating moiety. The compounds have been shown to have high
inhibitory activity.