A New Class of Diamine-Based Human Histamine H<sub>3</sub> Receptor Antagonists:  4-(Aminoalkoxy)benzylamines

Apodaca, Richard; Dvorak, Curt A.; Xiao, Wei; Barbier, Ann; Boggs, Jamin D.; Wilson, Sandy J.; Lovenberg, Timothy W.; Carruthers, Nicholas I.

doi:10.1021/jm030185v

Cited by 116 publications

(58 citation statements)

References 35 publications

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“…A second basic moiety usually boosts H 3 R affinity as has been shown with many compounds of the class of diamine-based ligands. [7][8][9] Computational models support an additional ionic interaction with transmembrane domain 5. 10,11) However, due to the strong receptor binding and their lipophilicity diamine-based ligands tend to accumulate centrally, which as a result might induce severe side effects and/or phospholipidosis.…”

Section: Regular Articlementioning

confidence: 93%

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

et al. 2010

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The histamine H 3 receptor (H 3 R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H 3 R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H 3 R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of g-pyranones with respect to the different moieties of the H 3 R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H 3 R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H 3 R ligands with a modified profile of action.

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Section: Regular Articlementioning

confidence: 93%

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

et al. 2010

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“…In the development of H 3 R antagonists intense modifications of its two basic structures and the spacer length 133) result in a great variety of diamine-based ligands. 134) A simple, but fundamental structure is dipiperidine JNJ-5207852 coming up as a preclinical candidate for sleep/wake and cognition disorders. JNJ-5207852 exhibits potent binding to rat (pK i ϭ8.9) and human (pK i ϭ9.2) H 3 R and a high selectivity over other GPCRs and ion channels.…”

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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“…[18] The potential liability of imidazole-containing compounds with respect to cytochrome P450 inhibition and drug-drug interactions led to the development of potent and selective non-imidazole derivatives, including compounds such as ABT-239 1, UCL 1972 2, JNJ-5207852 3, GSK-189254 4, Novo Nordisk's 5 and Merck's 6 ( Figure 1). [19][20][21][22][23] These intense efforts made by numerous pharmaceutical companies led to the development of a new refined H 3 antagonist pharmacophore model which contains three parts: a basic amine moiety (western part) able to interact with ASP3.32, an amino acid of the receptor [24], linked via a variable alkyl spacer to a central core, and an additional eastern part displaying a high chemical diversity ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Ceras

Cirauqui

Pérez‐Silanes

et al. 2012

European Journal of Medicinal Chemistry

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Abstract:The combination of antagonism at histamine H 3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H 3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H 3 antagonism affinity. However, since all these derivatives failed to block K ATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H 3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.

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A New Class of Diamine-Based Human Histamine H₃ Receptor Antagonists: 4-(Aminoalkoxy)benzylamines

Cited by 116 publications

References 35 publications

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

Histamine H3 Receptor Antagonists Go to Clinics

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

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A New Class of Diamine-Based Human Histamine H3 Receptor Antagonists: 4-(Aminoalkoxy)benzylamines

Cited by 116 publications

References 35 publications

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

Histamine H3 Receptor Antagonists Go to Clinics

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

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A New Class of Diamine-Based Human Histamine H₃ Receptor Antagonists: 4-(Aminoalkoxy)benzylamines