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Neelakandha S Mani - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of a Histamine H3 Receptor Antagonist—Manipulation of Hydroxyproline Stereochemistry, Desymmetrization of Homopiperazine, and Nonextractive Sodium Triacetoxyborohydride Reaction Workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Emily M Stocking, Nicholas I Carruthers, Aki Soyode-johnson, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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synthesis of a histamine H3 Receptor Antagonist manipulation of hydroxyproline stereochemistry desymmetrization of homopiperazine and nonextractive sodium triacetoxyborohydride reaction workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Aki Soyodejohnson, Emily M Stocking, Nicholas I Carruthers, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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a scalable synthesis of a histamine H3 Receptor Antagonist
Journal of Organic Chemistry, 2004Co-Authors: Neelakandha S Mani, Jill A Jablonowski, Todd K JonesAbstract:Starting from 1-methylimidazole, a concise, scalable, three-step synthesis of the title compound is described. The required 2-chloroimidazole was prepared in very good yield by halogen−metal exchange between the 2-lithio derivative and hexachloroethane.
Holger Stark - One of the best experts on this subject based on the ideXlab platform.
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procognitive properties of drugs with single and multitargeting H3 Receptor Antagonist activities
CNS Neuroscience & Therapeutics, 2014Co-Authors: Katarina Nikolic, Slavica Filipic, Danica Agbaba, Holger StarkAbstract:Summary The histamine H3 Receptor (H3R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3R Antagonists/inverse agonists involved studies of structure–activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoReceptors reinforces histaminergic transmission, while antagonism of H3 heteroReceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3R Antagonists/inverse agonists and dual H3R Antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.
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anxiolytic and antidepressant like activities of the novel and potent non imidazole histamine H3 Receptor Antagonist st 1283
Drug Design Development and Therapy, 2014Co-Authors: Amine Bahi, Holger Stark, Johannes Stephan Schwed, Miriam Walter, Bassem SadekAbstract:Previous studies have suggested a potential link between histamine H3 Receptors (H3R) signaling and anxiolytic-like and antidepressant-like effects. The aim of this study was to investigate the acute effects of ST-1283, a novel H3R Antagonist, on anxiety-related and depression-related behaviors in comparison with those of diazepam and fluoxetine. The effects of ST-1283 were evaluated using the elevated plus maze test, open field test, marbles burying test, tail suspension test, novelty suppressed feeding test, and forced swim test in male C57BL/6 mice. The results showed that, like diazepam, ST-1283 (7.5 mg/kg) significantly modified all the parameters observed in the elevated plus maze test. In addition, ST-1283 significantly increased the amount of time spent in the center of the arena without altering general motor activity in the open field test. In the same vein, ST-1283 reduced the number of buried marbles as well as time spent digging in the marbles burying test. The tail suspension test and forced swim test showed that ST-1283 was able to reduce immobility time, like the recognized antidepressant drug fluoxetine. In the novelty suppressed feeding test, treatment with ST-1283 decreased latency to feed with no effect on food intake in the home cage. Importantly, pretreatment with the H3R agonist R-α-methylhistamine abrogated the anxiolytic and antidepressant effects of ST-1283. Taken together, the present series of studies demonstrates the novel effects of this newly synthesized H3R Antagonist in a number of preclinical models of psychiatric disorders and highlights the histaminergic system as a potential therapeutic target for the treatment of anxiety-related and depression-related disorders.
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radiofluorinated histamine H3 Receptor Antagonist as a potential probe for in vivo pet imaging radiosynthesis and pharmacological evaluation
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Svetlana V Selivanova, Holger Stark, Michael Honer, Francine Combe, Kathleen Isensee, Stefanie D Kramer, August P Schubiger, Simon M AmetameyAbstract:Abstract The histamine H3 Receptor (H3R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer’s disease, schizophrenia, and narcolepsy. In vivo studies of the H3R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel 18F-labeled high-affinity H3R Antagonist 18F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8–20%, radiochemical purity >99%, and specific radioactivity >65 GBq/μmol. 18F-ST889 exhibited high in vivo stability and rather low lipophilicity (log D7.4 = 0.35 ± 0.09). In vitro autoradiography showed specific binding in H3R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with 18F-ST889 was not successful. Possible reasons are discussed.
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potential utility of histamine H3 Receptor Antagonist pharmacophore in antipsychotics
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Y Von Coburg, Xavier Ligneau, Tim Kottke, Lilia Weizel, Holger StarkAbstract:Abstract Histamine H3 Receptor (H3R) Antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional histamine H3 pharmacophore. The 4-(3-piperidinopropoxy)phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift affinity at dopamine D2-like Receptors (D2 and D3), to decrease affinity at histamine H1 Receptors, and to obtain H3R ligands with low nanomolar or subnanomolar affinity. Change of effects at D1-like Receptors (D1 and D5) were heterogeneous. With these newly profiled compounds different antipsychotic properties might be achieved.
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convenient procedures for synthesis of ciproxifan a histamine H3 Receptor Antagonist
Archiv Der Pharmazie, 2000Co-Authors: Holger StarkAbstract:Cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl methanone (ciproxifan) is a novel reference Antagonist for the histamine H3 Receptor. Despite the former Mitsunobu reaction the actual key reaction for preparation based on SNAr for acylated fluoroaromatics with an additional cyclization in a one-pot procedure needs no chromatographic purification steps and results in good yields.
Nicholas I Carruthers - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of a Histamine H3 Receptor Antagonist—Manipulation of Hydroxyproline Stereochemistry, Desymmetrization of Homopiperazine, and Nonextractive Sodium Triacetoxyborohydride Reaction Workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Emily M Stocking, Nicholas I Carruthers, Aki Soyode-johnson, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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synthesis of a histamine H3 Receptor Antagonist manipulation of hydroxyproline stereochemistry desymmetrization of homopiperazine and nonextractive sodium triacetoxyborohydride reaction workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Aki Soyodejohnson, Emily M Stocking, Nicholas I Carruthers, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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Exploration of structure-activity relationships for dual serotonin transporter reuptake inhibitors-histamine H3 Receptor Antagonists.
Current Topics in Medicinal Chemistry, 2010Co-Authors: Emily M Stocking, Pascal Bonaventure, Michael A Letavic, Nicholas I CarruthersAbstract:Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H3 Receptor Antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H3 Receptor Antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H3 Receptor Antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.
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Lead identification of acetylcholinesterase inhibitors–histamine H3 Receptor Antagonists from molecular modeling
Bioorganic & Medicinal Chemistry, 2007Co-Authors: Scott D Bembenek, Ann J Barbier, Leah Aluisio, Kirsten L Miller, Lisa Dvorak, Michael A Letavic, Timothy W Lovenberg, Richard Apodaca, John M. Keith, Nicholas I CarruthersAbstract:Abstract Currently, the only clinically effective treatment for Alzheimer’s disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H3 Receptor Antagonist. Both histamine H3 Receptor Antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H3 Antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs 2004, 18, 827]. Further, recent studies 2 indicate the peripheral anionic site (PAS) of AChE interacts with the β-amyloid (βA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of βA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor–histamine H3 Receptor Antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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A new class of diamine-based human histamine H3 Receptor Antagonists: 4-(aminoalkoxy)benzylamines.
Journal of Medicinal Chemistry, 2003Co-Authors: Richard Apodaca, Ann J Barbier, Sandy J Wilson, Jamin D Boggs, Timothy W Lovenberg, Curt A. Dvorak, Wei Xiao, Nicholas I CarruthersAbstract:4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H3 Receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be Antagonists in a cell-based model of human histamine H3 Receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H3 Receptor Antagonist.
Celestine T Oshaughnessy - One of the best experts on this subject based on the ideXlab platform.
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characterisation of the specific binding of the histamine H3 Receptor Antagonist radioligand 3h gr168320
European Journal of Pharmacology, 1996Co-Authors: J D Brown, Celestine T Oshaughnessy, Gavin J Kilpatrick, David I C Scopes, Paul Beswick, John W Clitherow, J C BarnesAbstract:Abstract We have examined the specific binding of the tritiated derivative of the potent histamine H 3 Receptor Antagonist, [3,4- 3 H 2 ]-cyclohexyl-{[4-(3 H -imidazol-4-yl)-piperidin-1-yl]iminomethyl}-amine ([ 3 H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [ 3 H]GR168320 at 37°C associated and dissociated rapidly. Binding was saturable ( B max 412 ± 89 fmol/mg protein) and of high affinity ( K d 0.12 ± 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H 3 Receptor agonists and Antagonists inhibited [ 3 H]GR168320 binding with high affinity. Agonist and Antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H 3 agonist radioligand N α -methylhistamine.
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pharmacological activity of vuf 9153 an isothiourea histamine H3 Receptor Antagonist
European Journal of Pharmacology, 1993Co-Authors: J C Barnes, J D Brown, Nicholas P Clarke, Jane Clapham, Deborah J Evans, Celestine T OshaughnessyAbstract:Abstract The pharmacological activity of the histamine H3 Receptor Antagonist VUF 9153 (S-[3-(4(5)-imidazolyl)]propyl-N-(4-chlorobenzyl) isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [ 3 H ]N α - methylhistamine binding to rat cortex/hippocampal membranes (pKi = 9.77±0.03) and antagonised the inhibitory responses to (R)-α-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pKB = 9.95 ± 0.07). In these assays, VUF 9153 was 10–50-fold more potent than the prototype H3 Receptor Antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H1 or H2 Receptors. Systemic administration of VUF 9153 (s.c. or p.o.) dose-dependently inhibited the ex vivo binding of [ 3 H ]N α - methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-α-methylhistamine. Calculation of ED50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered s.c. or p.o., was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective Antagonist for histamine H3 Receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H3 Receptors and can inhibit H3 Receptor-mediated functional responses in vivo.
Daniel J Pippel - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of a Histamine H3 Receptor Antagonist—Manipulation of Hydroxyproline Stereochemistry, Desymmetrization of Homopiperazine, and Nonextractive Sodium Triacetoxyborohydride Reaction Workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Emily M Stocking, Nicholas I Carruthers, Aki Soyode-johnson, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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synthesis of a histamine H3 Receptor Antagonist manipulation of hydroxyproline stereochemistry desymmetrization of homopiperazine and nonextractive sodium triacetoxyborohydride reaction workup
Journal of Organic Chemistry, 2010Co-Authors: Daniel J Pippel, Lana K Young, Michael A Letavic, Kiev S Ly, Bita Naderi, Aki Soyodejohnson, Emily M Stocking, Nicholas I Carruthers, Neelakandha S ManiAbstract:We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H3 Receptor Antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target’s core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa’s lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
