- Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists
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Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Gagginapally, Shankar Reddy,Kancharla, Durga Malleshwari,Middekadi, Vanaja Reddy,Bogaraju, Narsimha,Ravella, Srinivasa Rao,Singh, Pooja,Birangal, Sumit Raosaheb,Subramanian, Ramkumar,Palacharla, Raghava Choudary,Benade, Vijay,Muddana, Nageswararao,Jayarajan, Pradeep
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p. 4993 - 5008
(2018/05/29)
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- Synthesis of functionalised 4H-quinolizin-4-ones via tandem Horner-Wadsworth-Emmons olefination/cyclisation
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4H-Quinolizin-4-ones are a unique class of heterocycle with valuable physicochemical properties and which are emerging as key pharmacophores for a range of biological targets. A tandem Horner-Wadsworth-Emmons olefination/cyclisation method has been developed to allow facile access to substituted 4H-quinolizin-4-ones encoded with a range of functional groups.
- Muir, Calum W.,Kennedy, Alan R.,Redmond, Joanna M.,Watson, Allan J. B.
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supporting information
p. 3337 - 3340
(2013/06/05)
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- 2-Pyridinyl β-ketones as new ligands for roomerature CuI-catalysed C-N coupling reactions
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2-Pyridinyl β-ketones were identified as new efficient ligands for CuI-catalysed N-arylation of aliphatic amines at room temperature with great selectivity and substrate scope tolerance.
- Wang, Deping,Ding, Ke
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supporting information; experimental part
p. 1891 - 1893
(2009/10/23)
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- Two rare alkaloids from Pratia nummularia
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Two rare alkaloids, 1-(2-N-methylpiperidyl)-butan-2-one (1) and 1-(2-N-methylpiperidyl)-pentan-2-one (2), were identified from the medicinal plant Pratia nummularia. The structure of 1 was elucidated by means of spectroscopic methods. Compound 2 was established by spectral comparison with synthetic material.
- Ho,Ou,Sun,Sun
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p. 567 - 568
(2007/10/03)
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