Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities

Walczyński, Krzysztof; Guryn, Roman; Zuiderveld, Obbe P.; Timmerman, Henk

doi:10.1016/s0014-827x(99)00081-6

Cited by 40 publications

(14 citation statements)

References 36 publications

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“…The synthesis of the mono-substituted 2-benzazolpiperazines 5a,b,d has been described in the literature by reacting 2-chlorobenzazols 1a,b,d with excess piperazine hydrate ( 4 ) [ 15 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

et al. 2015

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We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1–1.0μM) over HDAC1 (IC50 = 0.9–6μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.

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Section: Methodsmentioning

confidence: 99%

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

et al. 2015

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“…Alkyl-substituted piperazine analog i.e. compound (221) (pA2 ¼ 7.02) is the most effective H 3 -receptor antagonist [260]. The structures for BTA as antihistaminic agents are tabulated in Fig.…”

Section: Bta As Antihistaminic Agentsmentioning

confidence: 99%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

482

238

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“…The development of novel, non‐imidazole ligands is an area of active research. Several ligand families ( Walczynski et al ., 1999 ; Linney et al ., 2000 ; Apelt et al ., 2002 ; Faghih et al ., 2002 ; Shah et al ., 2002 ) have been described. We set out to identify a novel H 3 antagonist that had suitable properties to evaluate the therapeutic potential of this target in humans.…”

Section: Introductionmentioning

confidence: 99%

Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H₃ antagonist

Barbier

Berridge

Dugovic

et al. 2004

British J Pharmacology

139

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1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H 3 receptor antagonist, with high affinity at the rat (pK i ¼ 8.9) and human (pK i ¼ 9.24) H 3 receptor. JNJ-5207852 is selective for the H 3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 mM. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED 50 of 0.13 mg kg À1 in mice). In vitro autoradiography with 3 H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3 H-R-amethylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3 H-JNJ-5207852 was observed in brains of H 3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg À1 s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H 3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wakepromoting effects of this H 3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg À1 i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H 3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H 3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H 3 receptor antagonists.

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Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities

Cited by 40 publications

References 36 publications

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H₃ antagonist

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Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities

Cited by 40 publications

References 36 publications

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H3 antagonist

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Product

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Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H₃ antagonist