Mini Reviews in Medicinal Chemistry - Volume 4, Issue 9, 2004

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.

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 Nα-methyl derivative. The discovery of histaprodifen (2-[2-(3,3- diphenylpropyl)-1H-imidazol-4-yl]ethanamine) and the novel lead compound suprahistaprodifen (Nα-2-[(1Himidazol- 4-yl)ethyl]histaprodifen) represents additional milestones in the H1-receptor agonist field.

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-Gsα 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.

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.

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.

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.

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.

This article describes recent developments in the synthesis and biological activity of α- aminoboronic acids, amine-carboxyboranes and their derivatives as potential therapeutic agents. α-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 α-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.