- Identification of novel GLUT inhibitors
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The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.
- Siebeneicher, Holger,Bauser, Marcus,Buchmann, Bernd,Heisler, Iring,Müller, Thomas,Neuhaus, Roland,Rehwinkel, Hartmut,Telser, Joachim,Zorn, Ludwig
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p. 1732 - 1737
(2016/07/27)
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- Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl) -2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and α-adrenolytic activity
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A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the α1 and α2-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pKi = 6.71 for α1-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED50 value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.
- Kulig, Katarzyna,Sapa, Jacek,Maciag, Dorota,Filipek, Barbara,Malawska, Barbara
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p. 466 - 475
(2008/12/21)
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- CYCLOHEXYLDIAMINES AS SELECTIVE ALPHA 1A/1D ADRENORECEPTOR ANTAGONISTS FOR THE TREATMENT OF BENIGN PROSTATE HYPERTROPHY AND LOWER URINARY TRACT SYMPTOMS
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The present invention relates to compounds of Formula (I) or a pharmaceutically acceptable form thereof, as dual selective a1a / a 1d adrenoreceptor antagonists for the treatment of benign prostatic hypertrophy and lower urinary tract symptoms. The present invention also relates to pharmaceutical compositions comprising said new compounds, new processes to prepare these new compounds and new uses as a medicine as well as method of treatments.
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Page/Page column 72-74
(2010/11/30)
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- New μ-opioid receptor agonists with phenoxyacetic acid moiety
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New μ-opioid receptor (MOR) agonists containing 4-hydroxypiperidine, piperidine and piperazine moieties were synthesized and evaluated to find a peripheral opioid analgesic. Among the synthesized compounds, [2-[1-[3-(N,N-dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxypiperidin-4-yl] phenoxy]acetic acid (8: SS620) having phenoxyacetic acid and 4-hydroxypiperidine moieties showed the highest agonist potency on the MOR in an isolated guinea-pig ileum preparation, and it also had selectivity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells compared with the same types of δ- and κ-opioid receptors (DOR and KOR). In addition, compound 8 showed a 10 times more potent MOR agonist activity than loperamide. Furthermore, compound 8 showed a peripheral analgesic activity in vivo screening on rat.
- Sato, Susumu,Komoto, Teruo,Kanamaru, Yoshihiko,Kawamoto, Noriyuki,Okada, Tomomi,Kaiho, Terumitsu,Mogi, Kinichi,Morimoto, Shinichi,Umehara, Norimitsu,Koda, Tadayuki,Miyashita, Akira,Sakamoto, Takao,Niino, Yasuhiro,Oka, Tetsuo
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p. 292 - 297
(2007/10/03)
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- New μ-opioid receptor agonists with piperazine moiety
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New μ-opioid receptor (MOR) agonists containing piperazine and homopiperazine moieties in the structures were synthesized and their affinities to and agonist potencies on MOR were evaluated. Among the synthesized compounds, 4-[4-(2-methoxyphenyl)piperazin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide (20Aa) showed the highest affinity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells, and the highest agonist potency on the MOR in isolated guinea-pig ileum preparation.
- Komoto,Okada,Sato,Niino,Oka,Sakamoto
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p. 1314 - 1320
(2007/10/03)
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