A new therapeutic approach in Alzheimer disease: Some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics

• Published in: Bioorganic & medicinal chemistry 2007-09, Vol.15 (17), p.5775-5786
• Main Authors: Gökhan-Kelekçi, Nesrin, Yabanoğlu, Samiye, Küpeli, Esra, Salgın, Umut, Özgen, Özen, Uçar, Gülberk, Yeşilada, Erdem, Kendi, Engin, Yeşilada, Akgül, Bilgin, A. Altan
• Format: Article
• Language: English
• Subjects: Alzheimer; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Analgesic-antiinflammatory activity; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Edema - drug therapy; Edema - pathology; Hindlimb - drug effects; Hydrogen Bonding; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Medical sciences; Mice; Models, Molecular; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - therapeutic use; Monoamine oxidase-A/B inhibition; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazole derivatives; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - therapeutic use; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.06.004

A novel series of pyrazole derivatives was synthesized and investigated for the inhibition of MAO-A and MAO-B. The compounds were also evaluated for their antiinflammatory and analgesic activity as well as ulcerogenic risk. The increasing life expectancy in our population makes Alzheimer’s disease (AD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that monoamine oxidase-B (MAO-B) inhibitors and antiinflammatory agents might be effective in treating AD. Therefore, a novel series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1 H)-pyrazole derivatives as promising MAO-B inhibitors was synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). Most of the synthesized compounds showed high activity against both the MAO-A (compounds 3e– 3h) and the MAO-B (compounds 3i– 3l) isoforms. All the synthesized compounds were also tested for their in vivo antiinflammatory activity by two different bioassays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were determined. The combined antiinflammatory data from in vivo animal models showed that compound 3k exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects. Since compound 3k exhibits both antiinflammatory-analgesic activity and MAO-B inhibition, it needs further detailed studies.