Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor antagonists

Faghih, Ramin; Dwight, Wesley; Pan, Jia Bao; Fox, Gerard B.; Krueger, Kathleen M.; Esbenshade, Timothy A.; McVey, Jill M.; Marsh, Kennan C.; Bennani, Youssef L.; Hancock, Arthur A.

doi:10.1016/s0960-894x(03)00118-5

Cited by 56 publications

(34 citation statements)

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“…[113][114][115][116][117] The piperidinyl moiety and related structures have meanwhile been approved by numerous groups. [118][119][120][121] One of the first and most prominent structures designed by such a replacement is the inverse H 3 R agonist tiprolisant, the former BF2.649 (Fig. 5), which shows high binding affinity (Ϫlog K i ϭ8.6).…”

Section: )mentioning

confidence: 99%

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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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Section: )mentioning

confidence: 99%

“…5). 118) In spite of an only moderate brain/blood ratio (0.5) that obviously arouses from its carboxamide moiety structure it possesses efficacy in cognition and especially ADHD models. 152) Due to QT prolongation A-329821 was sorted out from further development.…”

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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“…However, A-304121 only had modest effects on slow wave activity by EEG. Further SAR studies on the phenyl ring substitution [60][61][62][63] and amine group [57,58,63,64] of A-923 (19), led to the discovery of the biaryl derivatives such as 21-23. Compound 21 is another example of the importance of the cloning of the human H 3 receptor [14] since 21 is an order of magnitude less potent at the human recombinant H 3 receptor than at the native rat receptor (rH 3 pK i =7.55, hH 3 pK i =6.00) [63].…”

Section: -Aminopropanols and Related Ligandsmentioning

confidence: 99%

“…Compound 21 is another example of the importance of the cloning of the human H 3 receptor [14] since 21 is an order of magnitude less potent at the human recombinant H 3 receptor than at the native rat receptor (rH 3 pK i =7.55, hH 3 pK i =6.00) [63]. The pyrrolidine derivatives, A-331440 (22) (rH 3 pK i =7.87, hH 3 pK i =8.56) [65] and A-349821 (23) (rH 3 pK i =8.56, hH 3 pK i =9.31) [66], show less species differentiation. A-331440 was studied as an anti-obesity agent and showed a decrease in weight at 5 mg/kg, which is comparable to dexfenfluramine at 10 mg/kg [67].…”

Section: -Aminopropanols and Related Ligandsmentioning

confidence: 99%

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

Stocking

Letavic²

2008

CTMC

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The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.

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“…We have synthesized two potent and selective non-imidazole H 3 R antagonist/inverse agonists [2,3] with cognitive enhancing properties in rodents, A-317920 (furan-2-carboxylic acid (2-{4-[3-(4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl}-1-methyl-2-oxo-ethyl)-amide) and A-349821 (4-{4-[3-((2R,5R)-2,5-dimethylpyrrolidinyl)propoxy]phenyl}phenyl-morpholin-4-ylketone) [4,5], that were radiolabeled for additional H 3 R binding characterization. …”

Section: Introductionmentioning

confidence: 99%

Use of novel, non-imidazole inverse agonist radioligands to define histamine H3 receptor pharmacology

et al. 2005

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IntroductionThe binding characteristics of histamine H 3 receptors (H 3 Rs) have been determined using a variety of imidazole-based agonist and antagonist radioligands to date [1]. We have synthesized two potent and selective non-imidazole H 3 R antagonist/inverse agonists [2, 3] with cognitive enhancing properties in rodents, A-317920 (furan-2-carboxylic acid (2-{4-[3-(4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl}-1-methyl-2-oxo-ethyl)-amide) and A-349821 (4-{4-[3-((2R,5R)-2,5-dimethylpyrrolidinyl)propoxy]phenyl}phenyl-morpholin-4-ylketone) [4,5], that were radiolabeled for additional H 3 R binding characterization. Materials and methods Radiolabels[ 3 H]A-317920 (specific activity = 28.5 Ci/mmol) and [ 3 H]A-349821 (specific activity = 23.9 Ci/mmol) (Fig. 1) were synthesized at Abbott Laboratories. Radiolabeled [ 3 H]-(N)-a-methylhistamine ([ 3 H]-NaMH) was purchased from Perkin-Elmer Life Sciences (Boston, MA). Inflamm. res. 54, Supplement 1 (2005) S46-S47 Saturation and competition binding assaysMembranes from rat and human cerebral cortex or C6 H 3 R cell lines expressing either rat or human full length (445 amino acids) histamine H 3 Rs were prepared and binding assays performed in 50 mM Tris/5 mM EDTA pH 7.4 (TE) buffer, as previously described [4]. For saturation assays, membranes were incubated with varying amounts of [ 3 H]-NaMH, [ 3 H]-A-317920, or [ 3 H]-A-349821. For competition assays, membranes were incubated with approximately 0.5 nM of the radiolabel in the presence or absence of test compounds. All assays were incubated at 25°C for 30 min then terminated with ice cold TE buffer followed by three washes. Non-specific binding was determined by using 30 mM thioperamide. K d (saturation assay) and K i (competition assay) values were calculated using one site binding or one site competition curve fitting equations with Prism software (Graph Pad, San Diego, CA). Results and discussion[ 3 H]A-317920 demonstrates high affinity only for rat brain cortical and rat cloned H 3 Rs with respective K d values of 0.18 and 0.21 nM and B max values of 209 and 1672 fmol/mg protein (Table 1), which are greater than those B max values obtained with the agonist radioligand [ 3 H]NaMH (128 and

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Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor antagonists

Cited by 56 publications

References 19 publications

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Antagonists as Wake-Promoting and Pro-Cognitive Agents

Use of novel, non-imidazole inverse agonist radioligands to define histamine H3 receptor pharmacology

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